A canal was surgically created in the lower lip of male Sprague-Dawley rats and used as a reservoir for moist snuff. A total of 230 animals were randomized into six groups, five containing 40 rats and one containing 30 rats. After 2 wk of recuperation, the animals were treated as follows. Group I was initiated with 7,12-dimethylbenz(a)anthracene 3 times/wk for 4 wk followed by cotton pellet administration. Group II was initiated with 7,12-dimethylbenz(a)anthracene for 4 wk followed by snuff twice a day, 5 days/wk. Group III received snuff twice a day, 5 days/wk. Groups IV and V were initiated with 4-nitroquinoline N-oxide 3 days/wk for 4 wk. Thereafter Group IV received a cotton pellet, and Group V rats were treated with snuff twice a day, 5 days/wk. Group VI received a cotton pellet once a day, 5 days/wk. Treatment of all groups continued for a maximum of 104 wk. Group V rats had a significantly lower mean survival time than did the other groups because of the development of lip sarcomas in 66% of the rats as compared with 23% in Group II and 26% in Group III. One rat in each of Groups IV and VI developed lip sarcomas. The incidence of sarcomas in Group V as compared with the other groups is statistically significant (P less than 0.05 to 0.001). Spindle cell proliferation, a possible precursor lesion of lip sarcoma, was found in five rats of Group II, seven of Group III, and four of Group V. These results show that snuff has strong promoting capability with regard to the development of lip sarcomas after 4-nitroquinoline N-oxide initiation, but not after 7,12-dimethylbenz(a)anthracene initiation. Snuff by itself caused three squamous carcinomas of the palate, two squamous cell papillomas of the lip, and ten lip sarcomas (in 38 rats as compared with one lip sarcoma in 30 control rats), showing snuff to be carcinogenic for the lip and oral cavity.