OBJECTIVES: Trazodone is a multifunctional triazolopyridine drug with antidepressant, anxiolytic, sedative, and hypnotic properties. The current retrospective study was designed to investigate the effectiveness of trazodone for reducing acute psychomotor activation (PA) in patients with bipolar disorder (BD). We specifically reasoned that a parenteral route of administration could offer potential advantages in this clinical setting. METHODS: We assessed the effectiveness and safety of parenteral trazodone in a retrospective study conducted in 64 inpatients with BD and acute PA. The effectiveness assessment was the Clinical Global Impression Scale - Severity Of Illness (CGI-S) rated before the administration of parenteral trazodone (baseline) and at the end of treatment. A post-treatment reduction in CGI-S score ≥ 20% compared with baseline was considered as the primary outcome measure. RESULTS: Administration of parenteral trazodone was associated with significant improvements in CGI-S scores from baseline (5.4 ± 0.9) to the end of the study (4.2 ± 1.0; p < 0.001, Wilcoxon matched-pairs signed-ranks test). A total of 34 patients (53.1%) showed a post-treatment reduction in CGI-S score ≥ 20% compared to baseline. Multivariable binary logistic regression analysis using a forward selection procedure identified treatment duration (in days) as the only independent predictor of post-treatment reduction in CGI-S score ≥ 20% (odds ratio: 1.28; 95% confidence interval: 1.02-1.60, p <0.05). Adverse effects occurred in 13 (20.3%) patients. CONCLUSIONS: Parenteral trazodone is well-tolerated and effective in 53.1% of patients with BP and acute PA. Treatment duration was identified as an independent predictor of response in our sample.