This study aimed to evaluate the clinical effect of a resin denture base containing 20wt% surface prereacted glass ionomer (S-PRG) fillers on saliva fluoride concentrations as a surrogate evaluation of caries control. The study was a double-blind randomized clinical trial with a total of 110 participants aged 35-60 years who wore a removable partial resin denture for 1.5 years. Subjects were randomly assigned to receive a partial resin denture fabricated either with or without 20wt% S-PRG fillers (n = 55 per group). After 14 days of wearing the dentures, 5,000 ppm fluoride gel was applied nightly on both sides of the denture before storing it in a denture box overnight every night for 1.5 years. The salivary fluoride concentration was measured at baseline, on days 1, 14, and 15, and at 3 months and 1.5 years of wearing the denture. A significant increase in salivary fluoride concentration in the S-PRG denture group was observed from baseline to day 1, followed by a significant decrease to an approximate baseline level. After recharge with 5,000 ppm fluoride gel, salivary fluoride increased markedly on day 15 and remained elevated at month 3 through to 1.5 years. The resin denture base containing 20wt% S-PRG fillers demonstrated an initial fluoride release that increased saliva fluoride concentrations, but the fluoride release from within the material was short lived. The long-term effect of sustained fluoride release from the denture when combined with a regular fluoride recharge regimen may be beneficial for caries prevention.