Objective: The present in vitro study compared the effect of lipase enzyme on the surface topography of Resilon and gutta-percha cones. Method: Specimens of gutta-percha and Resilon cones were divided into experimental and control groups, one positive and one negative. Experimental groups were immersed in lipase. Positive controls were immersed in phosphate buffer saline, whereas specimens from negative controls were not immersed in any solution. All specimens were incubated at 37˚C for 96 hours and then examined under SEM for surface roughness, and scored by two independent observers. Results: A statistically significant difference among mean values was seen, with group II (Resilon/ lipase) showing the highest mean value of 2.675 ± 0.355, and group V (gutta-percha/unimmersed) having the lowest mean value of 1.375 ± 0.270. Keywords: gutta-percha, lipase, polycaprolactone, surface roughness, surface topography