Peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, plays a role in adipocyte differentiation, type II diabetes, macrophage response to inflammation and is suggested to influence carcinogen-induced colon cancer. Studies done in vitro and in vivo also revealed that PPARγ ligands might promote differentiation and/or regression of mammary tumors. To directly evaluate the role of PPARγ in mammary carcinogenesis, PPARγ wild-type (+/+) or heterozygous (+/−) mice were administered 1 mg 7,12-dimethylbenz[ a ]anthracene (DMBA) by gavage once a week for 6 weeks and followed for a total of 25 weeks. Compared with congenic PPARγ(+/+) littermate controls, PPARγ(+/−) mice had early evidence for increased susceptibility to DMBA-mediated carcinogenesis based on a 1.6-fold increase in the percentage of mice with skin papillomas, as well as a 1.7-fold increase in the numbers of skin papillomas per mouse ( P < 0.05). Similarly, PPARγ(+/−) mice also had a 1.5-fold decreased survival rate ( P = 0.059), and a 1.7-fold increased incidence of total tumors per mouse ( P < 0.01). Moreover, PPARγ(+/−) mice had an almost 3-fold increase in mammary adenocarcinomas ( P < 0.05), an over 3-fold increase in ovarian granulosa cell carcinomas ( P < 0.05), an over 3-fold increase in malignant tumors ( P < 0.02) and a 4.6-fold increase in metastatic incidence. These results are the first to demonstrate an increased susceptibility in vivo of PPARγ haploinsufficiency to DMBA-mediated carcinogenesis and suggest that PPARγ may act as a tumor modifier of skin, ovarian and breast cancers. The data also support evidence suggesting a beneficial role for PPARγ-specific ligands in the chemoprevention of mammary, ovarian and skin carcinogenesis.