BACKGROUND: Internationally, guidelines for depression recommend a stepped care approach, implying that antidepressant medication should not be offered as a first step treatment to patients with sub-threshold or mild depression. In the Netherlands, antidepressant prescribing rates in general practice as a first treatment step are considered to be high. The aim of this study was to evaluate the implementation of guideline recommendations on antidepressant prescribing. METHODS: A quasi-experimental study with a non-equivalent naturalistic control group and three years follow-up was performed in the general practice setting in the Netherlands. General Practitioners (GPs) participated in a national Quality Improvement Collaborative (QIC), focusing on the implementation of a guideline based model for a stepped care approach to depression. The model consisted of self-help and psychological treatment options for patients with milder symptoms as an alternative to antidepressants in general practice. Changes in antidepressant prescription rates of GPs were documented for a three-year period and compared to those in a control group of GPs, selected from an ongoing national registration network. RESULTS: A decrease of 23.3% (49.4%-26.1%) in antidepressant prescription rates for newly diagnosed patients with depressive symptoms was found within the intervention group, whereas no difference occurred in the reference group (50.3%-52.6%). The decrease over time was significant, compared to the usual care group (OR 0.44, 95% CI: 0.21-0.92). CONCLUSIONS: An implementation program using stepped care principles for the allocation of depression interventions resulted in reduced antidepressant prescription rates in general practice. GPs can change prescribing behaviour within the context of a QIC.