Our objective was to determine whether modafinil alleviates fatigue in patients with amyotrophic lateral sclerosis (ALS). A placebo controlled trial with a 3:1 modafinil:placebo randomization in doses up to 300 mg/day for 4 weeks was followed by 8 weeks of open maintenance treatment. The primary endpoint was the Clinical Global Impressions-Improvement Scale. Secondary endpoints were the Fatigue Severity Scale, Epworth Sleepiness Scale, Beck Depression Inventory, Role Function Scale, and visual analog scales. Analysis of covariance was used to assess change at Week 4. Thirty-two patients were randomized; 29 completed the 4-week trial. In intention to treat (ITT) analysis, the response was 76% for modafinil versus 14% for placebo. In a completer analysis, the modafinil response rate was 86%, and the placebo response rate remained 14%. The number needed to treat was 1.6 (ITT). No medically serious adverse events were reported. Modafinil may be a promising intervention for fatigue in ALS patients. Replication in a larger study is needed.