Introduction: The efficacy of antidepressants in the treatment of depression has been convincingly demonstrated in randomised trials. However, non-adherence to antidepressant treatment is common. Objective: To evaluate, from a societal perspective, the cost effectiveness of a pharmacy-based intervention to improve adherence to antidepressant therapy in adult patients receiving treatment in primary care. Methods: An economic evaluation was performed alongside a 6-month randomised controlled trial in The Netherlands. Patients who came to 19 pharmacies with a new prescription for a non-tricyclic antidepressant, i.e. those who had not received any prescription for an antidepressant in the past 6 months, were invited to participate. They were then randomly allocated to education and coaching by the pharmacist or to usual care. The coaching programme consisted of three contacts with the pharmacist, with a mean duration of between 13 and 20 minutes, and a take-home video reviewing important facts on depression and antidepressant treatment. The clinical outcome measures were adherence to antidepressant treatment measured using an electronic pill container (eDEM) and improvement in depressive symptoms measured using the Hopkins Symptom Checklist (SCL). Resource use was measured by means of questionnaires. The uncertainty around differences in costs and cost effectiveness between the treatment groups was evaluated using bootstrapping. Results: Seventy patients were randomised to the intervention group and 81 to the usual care group; of these, 40 in the intervention group and 48 in the control group completed all of the follow-up questionnaires. There were no significant differences in adherence, improvements in the SCL depression mean item score and costs over 6 months between the two treatment groups. Mean total costs (2002 values) were €3275 in the intervention group and €2961 in the control group (mean difference €315; 95% CI -1922, 2416). The incremental cost-effectiveness ratio associated with the pharmacist intervention was €149 per 1% improvement in adherence and €2550 per point improvement in the SCL depression mean item score. Cost-effectiveness planes and acceptability curves indicated that the pharmacist intervention was not likely to be cost effective compared with usual care. Conclusion: In patients starting treatment with antidepressants, there were no significant differences in adherence, severity of depression, costs and cost effectiveness between patients receiving coaching by a pharmacist and patients receiving usual care after 6 months. Considering the resources needed to implement an intervention like this in clinical practice, based on these results, the continuation of usual care is recommended.