A systematic review of prognostic factors in amyotrophic lateral sclerosis (ALS) highlights key factors influencing survival. Median survival from onset to death ranges from 20 to 48 months, with 10–20% of patients surviving over 10 years. Older age and bulbar onset are consistently associated with worse outcomes. Gender, diagnostic delay, and El Escorial criteria show conflicting data. Symptom progression rate is an independent prognostic factor, along with psychosocial factors, frontotemporal dementia (FTD), nutritional status, and respiratory function. Enteral nutrition's effect on survival remains unclear, while non-invasive positive pressure ventilation (NIPPV) improves survival. Biological markers of progression are not well established, though some may emerge in the future. Factors such as age, site of onset (bulbar vs. spinal), respiratory status, and disease progression rate are critical for clinical trial design. Patients with bulbar onset have a worse prognosis than those with spinal onset. Respiratory onset is a strong negative prognostic factor. Patients with lower limb onset may have a poorer prognosis due to increased risk of complications. Patients with incomplete motor neuron disease, such as pure lower motor neuron disease, have a better prognosis than those with classic ALS. Psychosocial factors, including mood and self-esteem, significantly affect survival. Patients with psychological distress have a higher risk of mortality. Cognitive impairment, particularly in frontotemporal lobar dementia, is associated with shorter survival. Nutritional status, as indicated by BMI, is a prognostic factor. Respiratory function, measured by forced vital capacity (FVC), is a key prognostic factor. Therapeutic interventions such as riluzole improve survival, while NIPPV is associated with better outcomes. Enteral nutrition's effect on survival is unclear. Multidisciplinary care and ALS centres show better prognosis, independent of other factors. Biological markers for progression are not well established, though some studies suggest potential markers. These findings have important implications for clinical trial design, emphasizing the need for accurate stratification based on age, respiratory status, and disease progression. Alternative trial designs, including natural history controls and minimization methods, are recommended. The use of El Escorial criteria for trial eligibility is questioned due to its limitations. Overall, several well-established prognostic factors exist, but further research is needed to refine their application in clinical practice.A systematic review of prognostic factors in amyotrophic lateral sclerosis (ALS) highlights key factors influencing survival. Median survival from onset to death ranges from 20 to 48 months, with 10–20% of patients surviving over 10 years. Older age and bulbar onset are consistently associated with worse outcomes. Gender, diagnostic delay, and El Escorial criteria show conflicting data. Symptom progression rate is an independent prognostic factor, along with psychosocial factors, frontotemporal dementia (FTD), nutritional status, and respiratory function. Enteral nutrition's effect on survival remains unclear, while non-invasive positive pressure ventilation (NIPPV) improves survival. Biological markers of progression are not well established, though some may emerge in the future. Factors such as age, site of onset (bulbar vs. spinal), respiratory status, and disease progression rate are critical for clinical trial design. Patients with bulbar onset have a worse prognosis than those with spinal onset. Respiratory onset is a strong negative prognostic factor. Patients with lower limb onset may have a poorer prognosis due to increased risk of complications. Patients with incomplete motor neuron disease, such as pure lower motor neuron disease, have a better prognosis than those with classic ALS. Psychosocial factors, including mood and self-esteem, significantly affect survival. Patients with psychological distress have a higher risk of mortality. Cognitive impairment, particularly in frontotemporal lobar dementia, is associated with shorter survival. Nutritional status, as indicated by BMI, is a prognostic factor. Respiratory function, measured by forced vital capacity (FVC), is a key prognostic factor. Therapeutic interventions such as riluzole improve survival, while NIPPV is associated with better outcomes. Enteral nutrition's effect on survival is unclear. Multidisciplinary care and ALS centres show better prognosis, independent of other factors. Biological markers for progression are not well established, though some studies suggest potential markers. These findings have important implications for clinical trial design, emphasizing the need for accurate stratification based on age, respiratory status, and disease progression. Alternative trial designs, including natural history controls and minimization methods, are recommended. The use of El Escorial criteria for trial eligibility is questioned due to its limitations. Overall, several well-established prognostic factors exist, but further research is needed to refine their application in clinical practice.