This study evaluated the biocompatibility of an unfilled, fluoride-releasing acrylic resin by subcutaneous implantation in guinea pigs. The experimental fluoride resin was compared to a nonfluoride, dental pit and fissure sealant (DELTON) of similar composition. Thirty-four male albino guinea pigs received four Teflon® tubes each, implanted in the dorsal area. The tubes were open at both ends, three contained the experimental fluoride resin and one held the nonfluoride resin. The tubes and surrounding tissue were excised in 1–2 cm blocks, by necropsy, at 14 and 84 days. Histological evaluation showed that inflammatory response was none-to-slight at 14 days for 95% of the fluoride and 100% of the nonfluoride specimens. Five percent of the fluoride specimens produced a moderate tissue response. At 84 days, inflammatory response was none-to-slight for 82.5% of the fluoride and 61.5% of the commercial nonfluoride specimens, while 17.5% of the fluoride and 38.5% of the nonfluoride specimens produced moderate tissue responses. Chi-squared analysis and Fisher's Exact test revealed no statistically significant difference (p ≤ 0.05) in tissue response between the two resins at either 14 or 84 days. Hence it is concluded that the experimental, fluoride-releasing resin produces a very mild subcutaneous tissue response and that its biocompatibility is comparable to that of a widely used nonfluoride dental resin. It can, therefore, be considered as having a high potential for biological safety as a dental restorative resin or adhesive, or for other biomedical applications. © 1993 John Wiley & Sons, Inc.