The efficacy of Short Psychodynamic Supportive Psychotherapy (SPSP) has not yet been compared with pharmacotherapy. A mega-analysis based on three original Randomized Clinical Trials (RCTs) was performed. Patients with (mild to moderate) major depressive disorder were randomized in (24 weeks) SPSP (n = 97), pharmacotherapy (n = 45), or their combination (n = 171). Efficacy was assessed by the Hamilton Depression Rating Scale (HDRS), Clinical Global Impression of Severity and of Improvement (CGI-S), the Symptom Checklist (SCL; depression subscale) and the Quality of Life Depression Scale (QLDS). Pearson chi(2) calculations were used to compare success rates. Analyses of covariance (ANCOVAs) were used to test inter-group differences. Success rates indicated that independent observers (HDRS) found no differences in symptom reduction between SPSP and pharmacotherapy (P = 0.214), but therapists (CGI-S, P = 0.026), and patients (SCL, P = 0.036) favored SPSP. Combined therapy was found superior to pharmacotherapy by all three (patients (P = 0.000), therapists (P = 0.024), independent observers (P = 0.024)). Independent observers (P = 0.062) and therapists (P = 0.430) found no differences between combined therapy and SPSP, but patients (P = 0.016) found combined therapy to be superior. As far as quality of life is concerned, success rates indicated that patients (QLDS) found no differences between SPSP and pharmacotherapy (P = 0.073) or between SPSP and combined therapy (P = 0.217). However, they found combined therapy superior to pharmacotherapy (P = 0.015). The results of the mega-analysis suggest that combined therapy is more efficacious than pharmacotherapy. SPSP and pharmacotherapy seem equally efficacious, except for some indications that patients and therapists favor SPSP for symptom reduction. Combined therapy and SPSP also seem equally efficacious, except that patients think that the first is better in symptom reduction.