Aim: To assess to what extent a high physical symptom count influences the effect of treatment for major depressive disorder (MDD), and whether or not actual comorbid medical conditions explain this relationship. Method: Secondary data-analysis on a cluster-randomized trial in primary care, comparing the effectiveness of collaborative care with care as usual (CAU). MDD was measured using the PHQ-9. The Physical Symptoms Questionnaire (PSQ) was filled out at baseline by 115 patients (77.2% of those who entered the trial). Multilevel logistic regression models were used to test whether a high physical symptom count predicted lack of response to treatment, adding interaction terms to test differential effects on collaborative care versus CAU. Results: A high physical symptom count negatively influenced the effect of both collaborative care and care as usual (no interaction). Specifically, a high physical symptom count predicted lack of response in both conditions at 3 (odds ratio = 6.8), 6 (OR = 4.1), and 9. months follow-up (OR = 6.4). This was not explained by chronic physical illness. Conclusion: In this RCT, patients with MDD accompanied by a high physical symptom count benefited less from treatment for MDD in primary care, regardless of the type of treatment (either collaborative care or CAU). This was not explained by the presence of comorbid medical conditions. Further research is needed to improve treatment for MDD accompanied by a high physical symptom count, although collaborative care for depression is still more effective than CAU for this group of patients. Trial registration: Dutch trial register ISRCTN15266438. © 2013 Elsevier Inc.