This study investigates the long-term outcomes of COVID-19, focusing on the association between iron dysregulation and inflammatory stress erythropoiesis with post-acute sequelae (PASC). The research involved 214 individuals infected with SARS-CoV-2, ranging from asymptomatic to severe cases, followed for up to one year from the onset of symptoms. Key findings include: 1. **Iron Dysregulation and Inflammation**: A multivariate signature detected beyond two weeks of disease onset, encompassing unresolved inflammation, anemia, low serum iron, altered iron-homeostasis gene expression, and stress erythropoiesis, differentiated those who reported PASC months later, regardless of COVID-19 severity. 2. **Whole-Blood Heme-Metabolism Signature**: A whole-blood heme-metabolism signature, enriched in hospitalized patients at 1–3 months post-onset, coincided with pronounced iron-deficient reticulocytosis. 3. **Immune Cell Abnormalities**: Prolonged immunological disruption was observed in moderate to severe COVID-19, with lymphopenia and low numbers of dendritic cells persisting in those with PASC. Single-cell analysis revealed iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. 4. **Correlation with PASC**: The signature of slow-resolving inflammation, iron dysregulation, and ineffective compensatory stress erythropoiesis was a strong early correlate of PASC more than 3 months later. 5. **Cellular Deconvolution**: Single-cell analysis identified the cells contributing to defective iron homeostasis, with monocytes showing preferential expression of iron-homeostasis genes and increased CD71 expression, indicating increased iron demand in proliferating lymphocytes. 6. **Long-Term Symptom Groups**: Patients with PASC had significantly lower serum iron and TSAT, higher reticulocyte counts, and elevated inflammatory markers (CRP and IL-6) compared to those without PASC at 3–5 months post-onset. The study suggests that unresolved inflammation and iron dysregulation, particularly in moderate to severe COVID-19, may contribute to PASC by affecting cellular iron mobilization and defective stress erythropoiesis. These findings provide insights into potential therapeutic strategies to mitigate PASC.This study investigates the long-term outcomes of COVID-19, focusing on the association between iron dysregulation and inflammatory stress erythropoiesis with post-acute sequelae (PASC). The research involved 214 individuals infected with SARS-CoV-2, ranging from asymptomatic to severe cases, followed for up to one year from the onset of symptoms. Key findings include: 1. **Iron Dysregulation and Inflammation**: A multivariate signature detected beyond two weeks of disease onset, encompassing unresolved inflammation, anemia, low serum iron, altered iron-homeostasis gene expression, and stress erythropoiesis, differentiated those who reported PASC months later, regardless of COVID-19 severity. 2. **Whole-Blood Heme-Metabolism Signature**: A whole-blood heme-metabolism signature, enriched in hospitalized patients at 1–3 months post-onset, coincided with pronounced iron-deficient reticulocytosis. 3. **Immune Cell Abnormalities**: Prolonged immunological disruption was observed in moderate to severe COVID-19, with lymphopenia and low numbers of dendritic cells persisting in those with PASC. Single-cell analysis revealed iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. 4. **Correlation with PASC**: The signature of slow-resolving inflammation, iron dysregulation, and ineffective compensatory stress erythropoiesis was a strong early correlate of PASC more than 3 months later. 5. **Cellular Deconvolution**: Single-cell analysis identified the cells contributing to defective iron homeostasis, with monocytes showing preferential expression of iron-homeostasis genes and increased CD71 expression, indicating increased iron demand in proliferating lymphocytes. 6. **Long-Term Symptom Groups**: Patients with PASC had significantly lower serum iron and TSAT, higher reticulocyte counts, and elevated inflammatory markers (CRP and IL-6) compared to those without PASC at 3–5 months post-onset. The study suggests that unresolved inflammation and iron dysregulation, particularly in moderate to severe COVID-19, may contribute to PASC by affecting cellular iron mobilization and defective stress erythropoiesis. These findings provide insights into potential therapeutic strategies to mitigate PASC.