Abstract Sertraline (SRT) has been shown to be an effective antidepressant in extensive clinical trial programs but data on plasma concentrations regarding clinical outcome and tolerability are lacking. Twenty-one out-patients of both sexes, with mean age of 50.23 years (S.D.=17.37), affected by major depressive disorder, recurrent (Diagnostic and Statistical Manual of Mental Disorder—IV, DSM-IV), were treated with 25–150 mg of SRT once a day (mean=66.26 mg, S.D.=30.50) for 30 days. Clinical evaluation was assessed at baseline (T0), after 15 days (T15), and then after 30 days (T30). Plasma samples for SRT level determination were collected at T30. Brief Psychiatric Rating Scale (BPRS), Hamilton Rating Scale for Depression (HRS-D), and Hamilton Rating Scale for Anxiety (HRS-A) showed a significant improvement during the study ( P<.01 vs. T0). The most commonly reported side effects were nausea (19%), cephalalgia (9.5%), dry mouth (9.5%), decreased libido (9.5%), tremor (4.7%), and tachycardia (4.7%). SRT plasma levels ranged from 2.82 to 112.20 ng/ml (mean=40.42 ng/ml, S.D.=26.93). No correlation between SRT plasma levels and clinical improvement or side effects were observed. Drug plasma level determination does not seem be strictly necessary from a clinical point of view but further research seems advisable in patients at risk like elderly and during long-term studies.