BACKGROUND: Many antimicrobial compounds in mouthwashes can have a negative impact on the oral microbiome. O-cymen-5-ol, a compound derived from a phytochemical, has a targeted mode of action and is being used as an alternative. However, its effect on the native oral microbiome is unknown. AIM: To assess the effect of a mouthwash formulated with o-cymen-5-ol and zinc chloride on the oral microbiome of healthy individuals. METHODS: A mouthwash formulated with o-cymen-5-ol and zinc chloride was administered to a cohort of 51 volunteers for 14 days, while another cohort of 49 volunteers received a placebo. The evolution of the oral microbiome in both groups was analysed using a metataxonomic approach. RESULTS: Analysis of the oral microbiome showed that the mouthwash selectively targeted potential oral pathogens while maintaining the integrity of the rest of the microbiome. Specifically, the relative abundance of several potentially pathogenic bacterial taxa, namely , , , , , , , (nodatum group) and (SR1) decreased, while the growth of , a nitrate-reducing bacterium beneficial for blood pressure, was stimulated. CONCLUSIONS: The use of o-cymen-5-ol and zinc chloride as antimicrobial agents in oral mouthwashes is a valuable alternative to classical antimicrobial agents.