Objective: Several small clinical trials have reported that the dopamine agonist pramipexole was beneficial in treating patients with schizophrenia. A confirmatory trial was conducted to test this hypothesis. Methods: This 16-week, multicenter, double-blind, randomized, placebo-controlled study included 200 subjects meeting DSM-IV-TR criteria for schizophrenia or schizoaffective disorder. Patients were randomized to receive either pramipexole (0.75 mg twice daily, n = 100) or placebo (n = 100) as an add-on to their regular antipsychotic treatment. The primary outcome measure was the total score on the Positive and Negative Syndrome Scale (PANSS); secondary outcome measures included PANSS subscale and cognitive functioning scores. Recruitment was performed in 30 sites in Romania and 1 site in the Republic of Moldova between January and June 2011. Results: Analysis of covariance models showed no significant difference between pramipexole and placebo for total PANSS (P > .99) and PANSS positive (P > .99), negative (P = .73), and general psychopathology (P = .99) subscale scores. Changes in Clinical Global Impressions-Severity of Illness scale and Brief Assessment of Cognition in Schizophrenia scores showed no significant difference between pramipexole and placebo. Conclusions: The results of this large randomized controlled trial indicated that pramipexole was not efficacious as an add-on to antipsychotic medications for schizophrenia. Trial Registration: ClinicalTrials.gov identifier NCT01320982.