Heme oxygenase-1 (Hmox1) catalyzes the rate-limiting step in heme degradation, releasing iron, carbon monoxide (CO), and biliverdin. The aim of the present study was to investigate Hmox1 as a possible mechanism underlying propolis cytotoxic effects in KB cells. Cells were cultured for 24, 48 and 72 hours and treated with propolis or SnCl 2 , known inducers of Hmox1 protein expression and activity. Propolis and SnCl 2 treatments decreased cell viability and induced Hmox1 expression. Furthermore, propolis increased LDH release and decreased dramatically reactive oxygen species (ROS) formation. Toxic effects of both propolis and SnCl 2 were reversed by tin-mesoporphirin (SnMP), a Hmox activity inhibitor. No significant effect was observed on p21 expression following propolis treatment. By contrast, SnCl 2 decreased ROS formation and increased p21 expression but did not affect LDH release. These results were further confirmed by the use of CO releasing molecule (tricarbonyldichlororuthenium dimer (II)) (CORM-II) treatment (10-40 μM). Our results suggest that propolis mediates KB cell cytotoxicity, in part by Hmox1 induction, and that KB cells are very sensitive to Hmox1 derived CO, a property that may be relevant for oral squamous cell carcinoma therapy.