BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a multifactorial autoimmune disease caused by genetic susceptibility and exposure to environmental factors. There is not sufficient evidence to estimate potential environmental risk factors for NMOSD; therefore, many predisposing factors may remain unknown. ObjectiveThe present study assessed the possible associations of ethnicity, socioeconomic status (SES), and stressful life events with NMOSD risk after adjustment for sex and age in an Iranian population. MethodsThis population-based case-control study included NMOSD cases and healthy controls in Tehran, Iran. Diagnosis of disease was confirmed by neurologists based on the 2015 International Consensus Criteria (ICC). Controls were sex-matched with cases and had no history of any neurological disorders. The telephone interviews were administered to gather pertinent data. Matched logistic regression was used to estimate unadjusted and adjusted odds ratio (ORs) and 95% confidence intervals (CIs) using SPSS. ResultsThis study recruited 153 NMOSD cases and 400 controls with the case-control ratio of 1: 2.61 and mean ages (SD) of 37.11 (10.90) and 33.67 (8.37) years, respectively (p < 0.001). Depression history (OR = 3.79; 95% CI (1.50 – 9.58), p = 0.01) and stressful life events including death of first-degree relatives (OR = 5.10; 95% CI (1.78 – 14.61), p < 0.01), family disruption (OR = 12.68; 95% CI) 3.53 – 45.46), p < 0.001), homelessness periods(OR = 4.35; 95% CI (1.18 – 14.74), p = 0.02), joblessness (OR = 4.24; 95% CI (1.91 – 5.15), p = 0.01), and divorce (OR = 14.18; 95% CI (1.91 – 23.15), p = 0.01) were more common among NMOSD cases than matched controls and may play a role in increasing risk of disease occurrence. Marriage (OR = 0.10; 95% CI (0.03 – 0.35), p < 0.001) and Conquer (Iranian national exam for university entrance) (OR = 0.31; 95% CI (0.11 – 0.88), p = 0.02) had a negative association with NMOSD risk. Other stressful life events including jail term, close family members’ serious disease or suicide, death of spouse, being in debt, getting fired from work, migration, and retirement had no relation with NMOSD risk (P > 0.05). The total stress number and load were not significantly associated with the risk of NMOSD (P > 0.05). Self-rated health status was significantly higher in controls (p < 0.001). Socioeconomic status (SES), parental ethnicity, and parental educational level during subjects’ adolescence were not among the significant predictors of NMOSD risk (P > 0.05). ConclusionNo association was identified between ethnicity, SES, and parental educational levels as risk factors for developing NMOSD in an Iranian population. The obtained evidence showed the association of some individual stressful life events like death of first-degree relatives, family disruption, homelessness periods, joblessness, and divorce with the risk of developing NMOSD while marriage had a negative association. Depression history was more common among cases than healthy controls and may play a role in increasing risk of NMOSD.