Background: Practice variation in the primary care treatment of depression may be considerable in the Netherlands, due to relatively small and unregulated practices. We adapted the collaborative care model for the treatment of Major Depressive Disorder (MDD) to accommodate existing practice variation and tested whether this had added value over Care as Usual (CAU). Methods: A cluster randomized controlled trial was conducted to compare an adapted target driven collaborative care model with Care as Usual (CAU). Randomization was at the level of 18 (sub)urban primary care centers. The care manager and GP were supported by a web-based tracking and decision aid system that advised targeted treatment actions to achieve rapid response and if possible remission, and that warned the consultant psychiatrist if such treatment advice was not followed up. Eligible patients had a score of 10 or higher on the PHQ9, and met diagnostic criteria for major depression at the subsequent MINI Neuropsychiatric interview. A total of 93 patients were identified by screening. They received either collaborative care (CC) or CAU. Another 56 patients received collaborative care after identification by the GP. The outcome measures were response to treatment (50% or greater reduction of the PHQ9-total score from baseline) at three, six, nine and twelve months, and remission (a score of 0-4 on the PHQ9 at follow-up). Results: Treatment response and remission in CAU were low. Collaborative care was more effective on achieving treatment response than CAU at three months for the total group of patients who received collaborative care [OR 5.2 ((1.41-16.09), NNT 2] and at nine months [OR 5.6 ((1.40-22.58)), NNT 3]. The effect was not statistically significant at 6 and 12 months. Limitations: A relatively high percentage of patients (36.5%) did not return one or more follow-up questionnaires. There was no evidence for selective non response. Conclusions: Our adapted target driven CC was considerably more effective than CAU for MDD in primary care in the Netherlands. The Numbers Needed To Treat (NNT) to achieve response in one additional patient were low (2-3), which suggest that introducing CC at a larger scale may be beneficial. The relatively large effects may be due to our focus on reducing practice variation through the introduction of easy to use web based tracking and decision aids. The findings are highly relevant for the application of the model in areas where practices tend to be small and for mixed healthcare systems such as in many countries in Europe. © 2012 Elsevier B.V. All rights reserved.