Occupational exposures are suspected of contributing to the risk of amyotrophic lateral sclerosis (ALS), but results of epidemiologic studies have been inconsistent. The authors prospectively assessed the relation between occupation and ALS mortality among more than 1 million participants in the Cancer Prevention Study II of the American Cancer Society. Follow-up from 1989 through 2002 identified 507 ALS deaths among men and 430 among women. Adjusted rate ratios were calculated by using Mantel-Haenszel weights and Cox proportional hazards. Among men, elevated ALS mortality was found for programmers (rate ratio = 4.55, 95% confidence interval: 1.46, 14.2; p = 0.009) and laboratory technicians (rate ratio = 1.96, 95% confidence interval: 1.04, 3.66; p = 0.04). Occupations previously associated with increased risk of ALS for which no increased risk was found included farmers, electricians, and welders, although the numbers of electricians (eight ALS deaths) and welders (two ALS deaths) were small. Among women, only machine assemblers had significantly increased ALS mortality (rate ratio = 2.81, 95% confidence interval: 1.05, 7.53; p = 0.04). Results, which suggest that male programmers and laboratory technicians and female machine assemblers may be at increased risk of death from ALS, should be interpreted cautiously, however, because they are based on small numbers.