The authors examined the association between restless legs syndrome (RLS) and DSM-IV major depressive disorder and panic disorder based on Wave III and IV of the Baltimore ECA follow-up study. Of 1071 participants, 1024 completed the RLS Questionnaire and Diagnostic Interview Schedule. Adjusted odds ratio for diagnosis of major depressive disorder (4.7, 95% confidence interval [1.6, 14.5]) and panic disorder (12.9 [3.6, 46.0]) and comorbidity of major depressive disorder and panic disorder (9.7 [1.4, 69.0]) in the past 12 months suggested a strong association between restless legs syndrome and major depressive disorder and/or panic disorder.