In addition to treating the motor symptoms of Parkinson's disease, the dopamine agonist pramipexole has shown an antidepressant effect. The trials, however, included patients with motor complications, raising the question of whether the antidepressant benefit represented only a treatment-related motor improvement. To address this issue, we have conducted a 14-week randomized trial comparing pramipexole with an established antidepressant in patients without motor complications. At seven Italian centers, 67 Parkinsonian outpatients with major depression but no history of motor fluctuations and/or dyskinesia received open-label pramipexole (at 1.5 to 4.5 mg/day) or sertraline (at 50 mg/day). In both groups, the Hamilton Depression Rating Scale (HAM-D) score decreased throughout 12 weeks of treatment, but in the pramipexole group the proportion of patients who recovered, as defined by a final HAM-D score ≤ 8,was significantly higher, at 60.6% versus 27.3% (p = 0.006). Patients' self-ratings improved in both groups. All adverse events were mild or moderate, but five patients (14.7%) withdrew from the sertraline group. Despite the absence of motor complications, the pramipexole recipients showed improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscore. We conclude that dopamine agonists may be an alternative to antidepressants in Parkinson's disease.