BACKGROUND Previous interview-based studies have suggested that exposure to neurotoxicants including metals might be related to ALS. METHODS We evaluated the relation of lead exposure to ALS, using both biological measures and interviews, in a case-control study conducted in New England from 1993 to 1996. Cases (N = 109) were recruited at two hospitals in Boston, MA. Population controls (N = 256) identified by random-digit dialing were frequency-matched to cases by age, sex, and region of residence within New England. RESULTS Risk of ALS was associated with self-reported occupational exposure to lead (odds ratio [OR] = 1.9; 95% confidence interval [CI] = 1.1-3.3), with a dose response for lifetime days of lead exposure. Blood and bone lead levels were measured in most cases (N = 107) and in a subset of controls (N = 41). Risk of ALS was associated with elevations in both blood and bone lead levels. ORs were 1.9 (95% CI = 1.4-2.6) for each microg/dl increase in blood lead, 3.6 (95% CI = 0.6-20.6) for each unit increase in log-transformed patella lead, and 2.3 (95% CI = 0.4-14.5) for each unit increase in log-transformed tibia lead. CONCLUSIONS These results are consistent with previous reports and suggest a potential role for lead exposure in the etiology of ALS.