The purpose of this study was to subject 2 carrier-based root filling products to a 4-month microbial challenge in a dog model with histologic markers to assess periapical inflammation and bacterial penetration of the 2 filling materials. Histologic evidence of bacterial penetration and periapical inflammation were the outcome parameters used to compare the products. Teeth were aseptically prepared and then filled with carrier-based Resilon (RealSeal 1 [RS-1], n = 25) or with carrier-based gutta-percha (Thermafil, n = 25) and were left exposed for 4 months. The first control group received a coronal seal over either RS-1 or Thermafil root fillings (n = 8). A second control group was instrumented and left completely empty (n = 8). Histologic evidence of periapical inflammation was observed in 29% of the Thermafil group and in 9% of the RS-1 group. This difference was only significant when controlling for a possible tooth position effect on inflammation presence (P < .05). Histologic evidence of bacterial penetration was present in 9% of the RS-1 group and in 70% of the Thermafil group. The difference in penetration rates between RS-1 and Thermafil was statistically significant when controlling for any dog or tooth position effects on bacterial penetration (P < .001). Furthermore, there was a statistically significant correlation between histologic evidence of inflammation and histologic evidence of infection (P = .002). RS-1 appeared to resist bacterial penetration more effectively than Thermafil under the conditions of this study.