The aim of this study was to investigate in vivo biocompatibility of Resilon, compared with gutta-percha, at short and long-term following implantation in a rat subcutaneous implantation model.Male Wistar rats were implanted subcutaneously with either Resilon or gutta-percha or were sham controls. Tissues were harvested at 8 days or 60 days after implantation and were evaluated histologically for inflammation and fibrous encapsulation. The severity of histologic injury, scored on a scale of 0-4 and quantitative analysis of the capsule wall thickness were determined for statistical analysis. Data were analyzed by Student t-test, one-way analysis of variance, Kruskal-Wallis or Mann-Whitney's tests as appropriate. A value of P ≤ 0.05 was considered statistically significant.No behavioral changes or visible signs of physical impairment were observed at 8 days or 60 days post-implantation. Histopathologic observation of the implanted sites at each time-point showed that both Resilon and gutta-percha implants induced foreign body reaction, showing minimal to mild inflammatory reactions in most cases, which diminished significantly with time. Compared with gutta-percha, the capsule wall was thinner (P < 0.05) after Resilon implantation at day 8 and significantly (P = 0.01) thicker at day 60. In addition, capsule wall thickness showed a trend to increase with time after implantation in the Resilon groups (P < 0.05), opposed to the significant decrease (P = 0.016) observed after implantation in the gutta-percha groups, suggesting lesser long-term biocompatibility of Resilon.Our findings validate Resilon as an in vivo biocompatible material. However, our data suggest that long-term biocompatibility of Resilon, despite validated, is inferior to that of gutta-percha control.