BACKGROUND: Patients undergoing maintenance hemodialysis frequently exhibit poor mental health. We studied the effects of frequent in-center and nocturnal hemodialysis on depressive symptoms and self-reported mental health. STUDY DESIGN: 1-year randomized controlled clinical trials. SETTING & PARTICIPANTS: Hemodialysis centers in the United States and Canada. 332 patients were randomly assigned to frequent (6-times-weekly) compared with conventional (3-times-weekly) hemodialysis in the Frequent Hemodialysis Network (FHN) Daily (n = 245) and Nocturnal (n = 87) Trials. INTERVENTION: The Daily Trial was a trial of frequent (6-times-weekly) compared with conventional (3-times-weekly) in-center hemodialysis. The Nocturnal Trial assigned patients to either frequent nocturnal (6-times-weekly) hemodialysis or conventional (3-times-weekly) hemodialysis. OUTCOMES: Self-reported depressive symptoms and mental health. MEASUREMENTS: Beck Depression Inventory and the mental health composite score and emotional subscale of the RAND 36-Item Health Survey at baseline and 4 and 12 months. The mental health composite score is derived by summarizing these domains of the RAND 36-Item Health Survey: emotional, role emotional, energy/fatigue, and social functioning scales. RESULTS: In the Daily Trial, participants randomly assigned to frequent compared with conventional in-center hemodialysis showed no significant change over 12 months in adjusted mean Beck Depression Inventory score (−1.9 ± 0.7 vs −0.6 ± 0.7; P = 0.2), but experienced clinically significant improvements in adjusted mean mental health composite (3.7 ± 0.9 vs 0.2 ± 1.0; P = 0.007) and emotional subscale (5.2 ± 1.6 vs −0.3 ± 1.7; P = 0.01) scores. In the Nocturnal Trial, there were no significant changes in the same metrics in participants randomly assigned to nocturnal compared with conventional hemodialysis. LIMITATIONS: Trial interventions were not blinded. CONCLUSIONS: Frequent in-center hemodialysis, as compared with conventional in-center hemodialysis, improved self-reported general mental health. Changes in self-reported depressive symptoms were not statistically significant. We were unable to conclude whether nocturnal hemodialysis yielded similar effects.