Guidelines recommend stepped and collaborative care models (SCM) for depression. We aimed to evaluate the effectiveness of a complex guideline-based SCM for depressed patients. German primary care units were cluster-randomised into intervention (IG) or control group (CG) (3:1 ratio). Adult routine care patients with PHQ-9 ≥ 5 points could participate and received SCM in IG and treatment as usual (TAU) in CG. Primary outcome was change in PHQ-9 from baseline to 12 months (hypothesis: greater reduction in IG). A linear mixed model was calculated with group as fixed effect and practice as random effect, controlling for baseline PHQ-9 (intention-to-treat). 36 primary care units were randomised to IG and 13 to CG. 36 psychotherapists, 6 psychiatrists and 7 clinics participated in SCM. 737 patients were included (IG: n = 569 vs. CG: n = 168); data were available for 60% (IG) and 64% (CG) after 12 months. IG showed 2.4 points greater reduction [95% confidence interval (CI): -3.4 to -1.5, p < 0.001; Cohen's d = 0.45] (adjusted PHQ-9 mean change). Odds of response [odds ratio: 2.8; 95% CI: 1.6 to 4.7] and remission [odds ratio: 3.2; 95% CI: 1.58 to 6.26] were higher in IG. Guideline-based SCM can improve depression care.