Our objective was to explore treatment effects in patient subgroups using post hoc analyses of data from part 2 of the dexpramipexole Phase II study. Subjects with amyotrophic lateral sclerosis (ALS) received dexpramipexole 300 mg/day or 50 mg/day for 24 weeks. Treatment effects on the slope of the revised ALS Functional Rating Score (ALSFRS-R) and Combined Assessment of Function and Survival (CAFS) were evaluated in dichotomized subgroups: riluzole use, gender, site of symptom onset. Other subgroups were dichotomized using median baseline values for age, ALSFRS-R, slow vital capacity, symptom duration, diagnostic delay, and progression rate. Results showed that there was a 21% reduction in ALSFRS-R decline favoring the 300-mg vs. 50-mg arm (p = 0.177); mean CAFS ranking was significantly higher in the 300-mg vs. 50-mg arm (52.4 vs. 41.1; p = 0.046). Trends were recapitulated in virtually all subgroups. Generally, ALSFRS-R decline was reduced and CAFS rankings were higher in the 300-mg vs. 50-mg arm across subgroups. CAFS rankings were significantly higher in the 300-mg vs. 50-mg arm among subjects with ALSFRS-R scores ≤35, symptom duration <18.7 months, or progression rate ≥ 0.7 points/month (p < 0.03). In conclusion, the observed benefit of 300- vs. 50-mg dexpramipexole on functional decline and survival was generally consistent among subjects regardless of baseline characteristics.