To evaluate the efficacy and safety of Streptococcus salivarius K12 as an adjuvant in treating oral candidiasis.A total of 56 patients were participated in the randomized, double-blinded, placebo-controlled clinical trial. The S. salivarius K12 or placebo lozenges plus nystatin tablets were given for up to 4 weeks at 1-week interval and then followed up for 1 week thereafter. We collected and analyzed the mycological and clinical data, treatment course, and safety data.At the end of the treatment, significant differences were found in the mycological cure rates between K12 group and control group (90.48% and 55.56%, respectively, p = 0.008). Survival analysis demonstrated no statistical difference in overall cure rates comprehensively considering mycological cure, clinical improvement, and recurrence (p = 0.078), while statistical difference was found in mycological cure (p = 0.013) between the two groups. The median treatment courses of K12 group and control group were 3 weeks and 4 weeks, respectively. No severe events were reported during the study.Streptococcus salivarius K12 exhibited potential efficacy and safety as an adjuvant in treating oral candidiasis by enhancing mycological cure and shortening the treatment course of conventional antifungal therapy in this randomized, double-blinded, placebo-controlled clinical trial. Further large-scale clinical studies are desired to accumulate more evidence for its clinical applications.