Isotretinoin-related risk of depression and suicidal behavior is a topic of inconclusiveness. A crucial knowledge gap exists in defining the association of isotretinoin with other psychiatric comorbidities. To evaluate the risk of psychiatric outcomes among patients with acne treated with isotretinoin versus oral antibiotics. A global population-based retrospective cohort study enrolled 2 groups of patients with acne managed by isotretinoin (n=75,708) and oral antibiotics (n=75,708). Patients were compared regarding the risk of 9 psychiatric outcomes. Relative to those treated with oral antibiotics, patients prescribed isotretinoin experienced lower risk of depression (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.87-0.93; P<.001), but comparable risk of major depressive disorder (HR, 0.97; 95% CI, 0.92-1.03; P=.318). Risk of suicidal attempts was comparable between groups (HR, 0.97; 95% CI, 0.85-1.11; P=.663), despite the elevated risk of suicidal ideation in those under isotretinoin (HR, 1.41; 95% CI, 1.32-1.50; P<.001). Patients under isotretinoin had lower risk of post-traumatic stress disorder (HR, 0.75; 95% CI, 0.68-0.82; P<.001), anxiety (HR, 0.84; 95% CI, 0.82-0.87; P<.001), bipolar disorder (HR, 0.65; 95% CI, 0.59-0.72; P<.001), schizophrenia (HR, 0.60; 95% CI, 0.48-0.76; P<.001), and adjustment disorder (HR, 0.82; 95% CI, 0.77-0.87; P<.001). Retrospective data collection. Isotretinoin confers lower risk of 6 psychiatric comorbidities and comparable risk of suicidal attempts.