N-methyl-D-aspartate (NMDA) receptor antibody encephalitis is a newly recognized autoimmune disorder associated with antibodies against the NMDA receptor, primarily affecting both sexes and often without an underlying tumor. This study describes the clinical and paraclinical progression of this condition in 44 patients, with 35/44 (80%) showing no detectable tumor. The disease progresses in two distinct stages: early features such as neuropsychiatric symptoms and seizures, followed by later features like movement disorders, reduced consciousness, and dysautonomia, with a median time gap of 10–20 days between the two stages. The early stage is associated with cerebrospinal fluid (CSF) lymphocytosis, while the later stage is marked by the appearance of oligoclonal bands. NMDA receptor antibodies are predominantly of the IgG1 subclass and can activate complement, leading to immune-mediated damage. Early immunotherapy significantly improves clinical outcomes, with better results observed in patients who received treatment within 40 days of symptom onset. Non-paraneoplastic patients who received no immunotherapy had poorer outcomes. The study highlights the importance of early diagnosis and treatment, as well as the need for long-term immunosuppression in some cases. The findings support a model of the disease occurring in two distinct clinical and neuropathological stages, with the early stage involving the diffusion of serum antibodies into the cortical grey matter and the later stage involving secondary immune expansion within the intrathecal compartment. The study also emphasizes the importance of distinguishing between paraneoplastic and non-paraneoplastic cases, as the treatment response and prognosis differ. Overall, the study provides valuable insights into the clinical spectrum, progression, and treatment of NMDA receptor antibody encephalitis.N-methyl-D-aspartate (NMDA) receptor antibody encephalitis is a newly recognized autoimmune disorder associated with antibodies against the NMDA receptor, primarily affecting both sexes and often without an underlying tumor. This study describes the clinical and paraclinical progression of this condition in 44 patients, with 35/44 (80%) showing no detectable tumor. The disease progresses in two distinct stages: early features such as neuropsychiatric symptoms and seizures, followed by later features like movement disorders, reduced consciousness, and dysautonomia, with a median time gap of 10–20 days between the two stages. The early stage is associated with cerebrospinal fluid (CSF) lymphocytosis, while the later stage is marked by the appearance of oligoclonal bands. NMDA receptor antibodies are predominantly of the IgG1 subclass and can activate complement, leading to immune-mediated damage. Early immunotherapy significantly improves clinical outcomes, with better results observed in patients who received treatment within 40 days of symptom onset. Non-paraneoplastic patients who received no immunotherapy had poorer outcomes. The study highlights the importance of early diagnosis and treatment, as well as the need for long-term immunosuppression in some cases. The findings support a model of the disease occurring in two distinct clinical and neuropathological stages, with the early stage involving the diffusion of serum antibodies into the cortical grey matter and the later stage involving secondary immune expansion within the intrathecal compartment. The study also emphasizes the importance of distinguishing between paraneoplastic and non-paraneoplastic cases, as the treatment response and prognosis differ. Overall, the study provides valuable insights into the clinical spectrum, progression, and treatment of NMDA receptor antibody encephalitis.