Abstract Background There is a lack of information on the cost-effectiveness of suicide prevention interventions. The current study examines the cost-effectiveness of a multifaceted structured intervention aiming to improve adherence to the national suicide practice guideline in comparison with usual implementation. Methods In the intervention condition, professionals of psychiatric departments were trained using an e-learning supported Train-the-Trainer program. Newly admitted suicidal patients were assessed as soon as their department was trained and at 3 months follow-up. The primary outcome was improvement in suicide ideation. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes were plotted, and cost-effectiveness acceptability curves were estimated. Results For the total group of suicidal patients (n=566), no effect of the intervention on suicide ideation or costs was found. For a subgroup of depressed suicidal patients (n=154, intervention=75, control=79), mean level of suicide ideation decreased with 2.7 extra points in the intervention condition, but this was not statistically significant. For this subgroup, the intervention may be considered cost-effective in comparison with usual implementation if society is willing to pay≥ € 6100 per unit of effect on the suicide ideation scale extra. Limitations Considering the cost outcomes, we had almost no cases that were complete, and heavily relied on statistical techniques to impute the missing data. Also, diagnoses were not derived from structured clinical interviews. Conclusions We presented the first randomized trial (trial registration: The Netherlands Trial Register (NTR3092 www.trialregister.nl)) on cost-effectiveness of a suicide practice guideline implementation in mental health care. The intervention might be considered cost-effective for depressed suicidal patients if society is willing to make substantial investments.