Background: Little is known about the influence of depressed patients’ preferences and expectations about treatments upon treatment outcome. We investigated whether better clinical outcome in depressed primary care patients is associated with receiving their preferred treatment. Methods: Within a randomized placebo-controlled single-centre 10-week trial with 5 arms (sertraline; placebo; cognitive-behavioral group therapy, CBT-G; moderated self-help group control; treatment with sertraline or CBT-G according to patients’ choice), outcomes for 145 primary care patients with mild-to-moderate depressive disorders according to DSM-IV criteria were investigated. Preference for medication versus psychotherapy was assessed at screening using a single item. Post-baseline difference scores for the Hamilton Depression Rating Scale (HAMD-17) were used to assess treatment outcome (mixed-model repeated-measures regression analysis). Results: Depressed patients receiving their preferred treatment (n = 63), whether sertraline or CBT-G, responded significantly better than those who did not receive their preferred therapy (n = 54; p = 0.001). The difference in outcome between both groups was 8.0 points on the HAMD-17 for psychotherapy and 2.9 points on the HAMD-17 for treatment with antidepressants. Results were not explained by differences in depression severity or dropout rates. Conclusions: Patients’ relative preference for medication versus psychotherapy should be considered when offering a treatment because receiving the preferred treatment conveys an additional and clinically relevant benefit (HAMD-17: +2.9 points for drugs; +8.0 points for CBT-G) in outcome.