This population-based case-control study was conducted in three counties in western Washington state (USA) between 1990 and 1994 to assess the association between amyotrophic lateral sclerosis (ALS) and several hypothesized risk factors, including a family history of neurodegenerative diseases, physical trauma (fractures, electrical shocks, and surgeries), rural residence, travel, and medical history. One hundred seventy-four cases with ALS, newly diagnosed by neurologists, were identified through several case-finding methods. Two controls (n = 348), who were matched to each case by gender and age (±5 years), were identified through random digit telephone dialing or Medicare lists. Exposure data were collected through structured in-person interviews. A greater proportion of cases (2.3%) than controls (0.9%) reported a first-degree relative with ALS, resulting in an odds ratio of 3.1 (95% CI, 0.6–15.7). For a positive family history of ALS among second-degree relatives, the odds ratio was 4.0 (95% CI, 1.0–16.6). Overall, reports of first- or second-degree relatives with ALS yielded a significantly elevated odds ratio of 3.3 (95% CI, 1.1–9.9). No association was found with a family history of Alzheimer’s disease or Parkinson’s disease, or with a family history of the neurodegenerative diseases as a group. No significant associations were demonstrated for any of the other factors analyzed, including a history of fractures, electrical shocks, or surgeries, a history of residence in rural areas, a history of travel to areas in the western Pacific where ALS is endemic, and a medical history of polio, polio immunization, or tetanus immunization.