Objective: To assess the microbiological effects of an antiseptic, non-alcohol based mouth-rinse containing chlorhexidine and cetylpyridinium chloride, in patients undergoing radiation therapy for head-and-neck cancer. Study Design: This was a parallel, double-blind, prospective, randomized clinical trial, including patients irradiated as part of the therapy of head-and-neck cancer, aged 18-75, with at least 10 teeth, and willing to sign an informed consent. Cancer patients were randomly assigned to one of the two treatments (test mouth-rinse or a placebo). Three visits were scheduled (baseline, 14 and 28 days). Microbiological findings were evaluated in tongue, mucosa and subgingival samples, by means of culture. Microbiological variables were assessed by means of the Mann-Whitney, Wilcoxon and chi-square tests. Results: 70 patients were screened and 36 were included. The detection of Candida species in mucosa and tongue samples showed significant reductions in the test group. Total bacterial counts decreased in both groups from baseline to the 2-week visit, while minor changes occurred between 2 and 4 weeks (effects on P. gingivalis, P. intermedia, C. rectus, E. corrodens). Conclusions: Within the limitations of the small sample size, this study suggests that the use of the tested mouth-rinse may lead to improvements in microbiological parameters in patients irradiated for head-and-neck cancer. © Medicina Oral S. L.