The aim of this study was to evaluate the clinical efficacy and safety of a dental drug delivery system (3DS) for the selective reduction of mutans streptococci. Twenty patients with high levels of mutans streptococci in saliva participated. The efficacy of 0.2% chlorhexidine (CHX) delivered by 3DS in reducing the salivary levels of mutans streptococci compared with total streptococci and lactobacilli was investigated. Each subject was treated by professional mechanical tooth cleaning (PMTC) and subsequently individual trays with CHX for 5 min. Salivary bacterial samples were taken at the baseline and weeks 1-12. A significant reduction in the colony count of mutans streptococci was observed during the first 4 weeks compared with the baseline count, while no significant decrease in the count of total streptococci or lactobacilli was found during 12 weeks. In particular, the proportion of mutans streptococci in total streptococci remained low after 12 weeks. Our results indicate that the new 3DS used in combination with PMTC appears to be a promising intraoral drug delivery system which, when used with a low CHX concentration selectively, effectively reduces mutans streptococci in the oral cavity with no adverse effects.