Background Many mood disorder patients need analgesics due to increased pain sensitivity. Recent studies have suggested that nonsteroidal anti‐inflammatory drugs (NSAIDs) may inhibit antidepressant treatment, which requires replication before clinical recommendations. Methods The Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study randomized participants to 6 months lithium or quetiapine treatment. Use of NSAIDs and paracetamol was assessed throughout the study period and psychopathology measured with the Clinical Global Impression Scale for Bipolar Disorder (CGI‐BP) and Bipolar Inventory of Symptoms Scale (BISS). The effects of NSAIDs and paracetamol on treatment outcome were examined using mixed effects linear regression adjusted for age, gender, body mass index, smoking status, exercise, and somatic diseases. Results Among 482 participants, 177 (36.7%) used NSAIDs and/or paracetamol during the study. NSAID and paracetamol users did not differ from nonusers with respect to treatment outcome with lithium or quetiapine at any time point during 6 months treatment on the overall CGI‐BP (β = 0.001 (95% CI = −0.01 to −0.01), P = .87), the BISS (β = 0.01 (95% CI = −0.17 to 0.15), P = .91), nor the CGI‐BP subscales for depression or mania. Users of NSAIDs only (n = 76), paracetamol only (n = 62), and users of both NSAIDs and paracetamol (n = 39) showed no statistical difference compared to nonusers (all P > .3). Conclusions This is the first trial to show that use of NSAIDs and paracetamol, alone or in combination, does not affect lithium‐ or quetiapine‐based bipolar disorder mood‐stabilizing treatment outcomes. Prior studies have suggested that NSAIDs may inhibit antidepressant treatment, whereas our results support findings indicating no detrimental effects of NSAIDs or paracetamol on affective disorder treatment.