Amyotrophic lateral sclerosis (ALS) most likely results from a multifactorial gene-environment interaction. Strenuous physical activity and occupational exposures have been suggested to play a role, and an abnormal response to hypoxia has been proposed in ALS pathogenesis. To test the hypothesis of an excess risk in occupations typically leading to intermittent hypoxia at the tissue level, we accessed a large publicly available database, including death certificates from 24 U.S. states in 1984-1998. We conducted a case-control analysis of 14,628 deaths due to ALS therein reported and 58,512 controls deceased from other selected causes of death, frequency matched by age, gender and broad geographic area. ALS risk associated with physical activity, and occupations leading to intermittent hypoxia, such as fire fighters and professional athletes, were calculated with unconditional logistic regression, adjusting by age, marital status, residence, and socioeconomic status. Physical activity in general did not show an association with ALS risk. Risk associated with occupation as a professional athlete was elevated (OR = 1.81, 99% CI 0.69-4.78), but not significantly so. Fire fighters showed a significant two-fold excess ALS risk (OR = 2.0; 99% CI 1.2-3.2). Based on our findings and the current clinical, epidemiological and experimental evidence, we suggest that occupational conditions typically leading to intermittent hypoxia, such as fire fighting, might be an ALS risk factor in subjects genetically prone to an abnormal response to hypoxia.