Background: Toxicity is a major concern related to the clinical use of polymyxin B, and available safety data for renal transplant patients are limited. Aims: We investigated the safety of polymyxin B and toxicity risk factors in renal transplant patients. Methods: A prospective study was performed on a group of renal transplant patients who received intravenous polymyxin B between January 2018 and August 2021. Polymyxin B treatment was monitored to evaluate toxicity and risk factors. Results: A total of 235 courses of polymyxin B were administered to 213 patients. Of these, 121 (51.5%) developed skin hyperpigmentation (SH), 149 (63.4%) developed neurotoxicity and 10 (5.5%) developed acute kidney injury of which 80% was reversible. Risk factors for developing SH included a high total dose by weight (odds ration [OR] 1.31, 95% confidence interval [CI] 1.08–1.60, P =.008) and the presence of neurotoxicity (OR 2.86, 95% CI 1.56–5.26, P =.001). Neurotoxicity manifested during the first 2 days of treatment. Neurotoxicity occurred most commonly in women (OR 3.84, 95% CI 1.82–8.10, P <.0001), and the presence of SH (OR 1.98, 95% CI 1.13–3.46, P =.016) was also an independent risk factor. Conclusions: Neurotoxicity and SH are the two major adverse effects of polymyxin B in renal transplant patients, which may limit its clinical use. [ABSTRACT FROM AUTHOR]