Objectives: To evaluate changes over time in drug use among patients undergoing Roux-en-Y gastric bypass (RYGB) surgery and a matched population-based comparison cohort. Background: A little is known about the prescription drug use before and after RYGB surgery. Methods: Nationwide population-based cohort study included 9908 patients undergoing RYGB in Denmark during 2006 to 2010 and 99,080 matched general population members. We calculated prevalence ratios (PRs) comparing prescription drug use 36 months after RYGB/index date with use 6 months before this date (baseline). Results: At baseline, more RYGB patients (median 40 years, 22% males) used a prescription drug (81.5% vs 49.1%). After 3 years, the use had decreased slightly among RYGB patients [PR = 0.93; 95% confidence interval (CI) = (0.91, 0.94)], but increased in the comparison cohort (PR = 1.05; 95% CI = 1.04-1.06). In the RYGB cohort, large, sustained decreases occurred for treatment of metabolic syndrome-related conditions, such as any glucose-lowering drug (PR = 0.28; 95% CI = 0.25-0.31) and lipid-modifying drugs PR = 0.50; 95% CI = 0.46-0.55). Use of inhalants for obstructive airway diseases (PR = 0.79; 95% CI = 0.74-0.85) also decreased. Use of neuropsychiatric drugs was two-fold higher at baseline in the RYGB cohort (22.8% vs 10.9%) and increased further after RYGB-that is, antidepressants (PR = 1.13; 95% CI = 1.07-1.19), antipsychotics (PR = 1.39; 95% CI = 1.21-1.60), and potential treatment of neuropathy (PR = 1.39; 95% CI = 1.28-1.51). Conclusions: Three years after RYGB surgery, we found large reductions in the use of treatment of metabolic syndrome-related conditions, inhalants for obstructive airway diseases and glucocorticoid use. In contrast, frequent use of neuropsychiatric drugs further increased after RYGB.