OBJECTIVE This study was conducted to determine the possible carcinogenic role of N-Nitrosonornicotine (NNN) when combined with subcarcinogenic doses of strong carcinogens dimethylbenz (a) anthracene (DMBA) and 4-nitroquinoline-N-oxide (4NQO) in the hamster cheek pouch. METHODS Eighty-five Syrian golden hamsters were randomly divided into three main groups. Group A contained 35 animals, 20 of which were treated with 0.1% DMBA followed by 4% NNN (A-I), 5 with 0.1% DMBA (A-II), 5 with 4% NNN (A-III), and 5 with mineral oil alone (A-IV). Group B contained 23 animals, 13 of which were treated with 0.5% 4NQO followed by 4% NNN (B-I), 5 with 0.5% 4NQO (B-II), and 5 animals with propyleneglycol alone (B-III). Group C contained 27 animals, 14 of which were treated with 0.1% DMBA followed by 4% NNN and 0.5% 4NQC (C-I), and 13 with 0.1% DMBA followed by 0.5% 4NQO (C-II). All animals were treated three times per week for 16 weeks. A total of 7 animals died during this period. RESULTS Squamous cell carcinoma (SCCA) developed in eight animals (67%) in the group treated with all three chemicals (C-I), in four animals (33%) treated with DMBA and 4NQO (C-II), in two animals (15%) treated with 4NQO and NNN (B-I), and in two animals (11%) treated with DMBA and NNN (A-I). The difference between the number of animals that developed carcinoma in group C-I and those in groups A-I and B-I was statistically significant (P < .05) and this difference reached a significant value when group C-I and C-II were compared (P < or = .1). There was a direct relationship between the number of tumors produced in animals and the number of different chemicals applied. CONCLUSIONS The results of this study indicate that NNN, when combined with subcarcinogenic doses of other strong carcinogens, is a promoter in the development of squamous cell carcinoma and that 4NQO in 0.5% concentration is a stronger carcinogen than 0.1% DMBA.