We performed a historical cohort study of 307 untreated patients with probable or definite amyotrophic lateral sclerosis in order to investigate whether the mortality risk changed during the disease course and to identify prognostic factors at diagnosis. Patients were diagnosed in one of the academic hospitals in The Netherlands and followed-up for at least 6 years after diagnosis. The median survival from diagnosis was 1.4 years (95% confidence interval, 1.3-1.6 years) with an estimated 5- and 10-year survival of 20 and 8%, respectively. Mortality was at its maximum in the second year after diagnosis and declined considerably thereafter. Observed mortality approached the expected mortality in patients who survived diagnosis 6 or more years. In univariate and multivariate analyses, young age, limb onset, and a long delay between initial weakness and diagnosis were associated with lower mortality. The better prognosis of limb-onset patients was not observed in females. Patients with initial respiratory muscle weakness, had the worst prognosis with a median survival of only 2 months. The significantly greater mortality of older patients proved not to result from a rise in expected mortality only. In conclusion, the annual mortality risk in ALS does not remain constant throughout the disease and depends on age at diagnosis, site of onset, diagnostic delay, but also on the time since diagnosis. These findings may have consequences for the planning of symptomatic care and the design and analysis of therapeutic trials.