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Objective: To report an observational study of depression in a large cohort of patients with amyotrophic lateral sclerosis (ALS), including its prevalence, associations, longitudinal course, and effect on survival., Methods: The Patient Health Questionnaire-9 (PHQ-9) (a validated depression instrument) and other self-reported measures were obtained from patients with ALS as part of routine clinical care via tablet devices using a software system (Knowledge Program). Cox proportional hazard models, linear models, mixed effects models, and logistic regression were used for statistical analyses., Results: Of 1,067 patients seen over an 8-year period, 964 had at least one PHQ-9 recorded. Initially, at least moderate (PHQ-9 ≥ 10), moderately severe (PHQ-9 ≥ 15), and severe depression (PHQ-9 ≥ 20) were found in about 33%, 14%, and 5% of patients, respectively. Higher initial PHQ-9 was significantly predictive of mortality (hazard ratio 1.041 per increasing point, 95% confidence interval 1.018-1.065) after controlling for covariates. PHQ-9 was also associated with poorer quality of life. More advanced disease initially and pseudobulbar affect were associated with depression. In 587 patients with repeated PHQ-9 measures, worsening depression was not observed., Conclusion: Depression is prevalent in ALS and is associated with disease severity at initial assessment. Paradoxically, however, worsening depression is not observed during follow-up despite motor progression. Most importantly, depression has detrimental effects on survival and quality of life. Treatment of depression is recommended in ALS, although it is unknown if this would improve survival., (© 2016 American Academy of Neurology.)