OBJECTIVES: This study determined the efficacy of alcohol-free 0.05% cetylpyridinium chloride (CPC) mouthwash as an adjunct to twice-daily toothbrushing in comparison with 0.12% chlorhexidine gluconate (CHX) mouthwash and a placebo in reducing plaque accumulation and gingival inflammation. The side effects of the mouthwashes were also determined. MATERIALS AND METHODS: A double-blind, parallel, randomized control trial was conducted with 219 university students who were divided into three trial groups using block randomization: CPC, CHX and placebo groups. Clinical oral examinations to assess dental plaque accumulation (modified Quigley-Hein Plaque Index), gingival health (Löe and Silness Gingival Index) and tooth staining (modified Lobene Stain Index) were performed at baseline and at 6 weeks. RESULTS: Plaque and gingivitis scores were not significantly different among participants at baseline. After 6 weeks, plaque and gingivitis scores between the CPC and placebo groups and between the CHX and placebo groups were found to be significantly different. However, there was no significant difference between the CPC and CHX groups. The staining scores of participants in the CPC group were lower than those in the CHX group, but the difference was not significant. Taste alteration and numbness were more common among participants in the CHX group than in the CPC group. No significant difference in the perception of a burning sensation was observed. CONCLUSIONS: The 0.05% CPC mouthwash was as efficient as 0.12% CHX mouthwash in reducing dental plaque accumulation and gingival inflammation with fewer side effects, supporting its use as an adjunct to toothbrushing.