Chemomechanical caries removal allies an atraumatic technique with antimicrobiotic characteristics, minimizing painful stimuli and maximally preserving healthy dental structures. The purpose of this study was to compare the cytotoxic effects of papain-based gel (Papacarie) and another caries-removing substance, Carisolv, to a nontreatment control on cultured fibroblasts in vitro and the biocompatibility in subcutaneous tissue in vivo. The cytotoxicity analysis was performed on fibroblast cultures (NIH-3T3) after 0-, 4-, 8-, and 12-hour exposure (cell viability assay) and after 1-, 3-, 5-, and 7-day exposure (survival assay). In the in vivo study, the 2 compounds were introduced into polyethylene tubes that were implanted into subcutaneous tissues of rats. After 1, 7, 14, 30, and 60 days, tissue samples were examined histologically. Cell viability did not differ between the 2 experimental groups. The control group, however, showed significantly higher percentage viability. There were no differences in cell survival between the control and experimental groups. The histological analysis revealed a moderate inflammatory response at 2 and 7 days and a mild response at 15 days, becoming almost imperceptible by 30 and 60 days in both experimental groups. The 2 tested substances exhibited acceptable biocompatibilities and demonstrated similar responses in the in vitro cytotoxicity and in vivo implantation assay.