1) Objectives: - To systematically evaluate the effectiveness of pharmacist care compared with usual care (UC) on improving adherence to antidepressants in depressed outpatients. - To evaluate the effectiveness and cost‐effectiveness of a community pharmacist intervention (CPI) compared to UC in the improvement of adherence to antidepressants and patient wellbeing in a primary care population initiating treatment with antidepressants. 2) Methods: A systematic review and meta‐analysis of randomized controlled trials (RCTs) that evaluated the impact of pharmacist interventions on improving adherence to antidepressants was conducted. RCTs were identified through electronic databases and manual search. Methodological quality was assessed and methodological details and outcomes were extracted in duplicate. A RCT comparing patients with depressive disorder receiving a low intensity CPI (87) with patients receiving UC (92) was performed in Barcelona. The intervention consisted of an educational programme focused on improving knowledge about medication, improving patients’ compliance and reducing stigma. Measurements took place at baseline, 3 and 6 months. Adherence was continuously registered from the computerized pharmacy records. Secondary outcomes included clinical severity of depression (PHQ‐9), health‐related quality of life (HRQOL) (EuroQol‐5D) and satisfaction with the treatment received. Direct and indirect costs were assessed using the Client Service Receipt Inventory. Unit costs were derived from official local sources. Quality‐Adjusted Life‐Years (QALYs) were calculated using the EuroQol‐5D Spanish tariffs. 3) Results: Six RCTs were identified in the systematic review; most of them were conducted in the USA. A total of 887 depressed patients who were initiating or maintaining treatment with antidepressants and who received pharmacist care (459 patients) or UC (428 patients) were included in the review. The most commonly reported interventions were patient education and monitoring, monitoring and management of toxicity and side effects and compliance promotion. Overall, no statistical heterogeneity or publication bias was detected. The pooled odds ratio was 1.64 (95% CI 1.24‐2.17). Subgroup analysis showed no statistically significant differences in results. Results from the RCT showed that patients in the CPI group were more likely to remain adherent at 3 and 6‐month follow‐up but the difference was not statistically significant. No statistically significant differences were observed in clinical symptoms or satisfaction with the pharmacy service. However, patients in the CPI group showed greater statistically significant improvement in HRQOL compared to UC patients, both in the ITT and PP analyses. Overall costs were higher in the CPI group than in UC patients, mainly because of differences in productivity losses. There were no statistically significant differences between groups in QALYs. From the societal perspective, the incremental cost‐effectiveness ratio (ICER) for CPI compared with UC was €9,335 per extra adherent patient. The incremental cost‐utility ratio (ICUR) was €38,896 per QALY gained. If willingness to pay (WTP) is €50,000 per one extra adherent patient, per extra remission of symptoms or per QALY, the probability of the CPI being cost‐effective was 0.71, 0.52 and 0.56, respectively. From the healthcare perspective, the ICER was €862 per extra adherent patient. ICUR was €3,542. The probability of the intervention being cost‐effective was 0.75 if WTP is €12,000 for an extra adherent patient and €40,000 for QALY gained. The probability of the CPI being cost‐effective in remission of depressive symptoms was 0.55 for a WTP of €50,000. 4) Conclusions: A pharmacist intervention could be a good strategy to improve patients’ adherence to antidepressants in primary care but evidence supporting the pharmacist intervention in depressed patients is still limited, especially in community pharmacies and outside the USA. A low intensity CPI proved to be ineffective in improving patients’ adherence to antidepressants or clinical symptomatology. However, it was effective in improving the patient’s HRQOL. The CPI was not cost‐effective in comparison with UC in the improvement of adherence, depressive symptoms and QALYs.