p16 is an important tumor suppressor gene, which is inactivated in many kinds of tumors. The common variants of p16 may be associated with the risk of certain tumors development. We analyzed the frequency of two adjacent polymorphisms in p16 exon 3 (540C→G and 580C→T) and their haplotype in blood samples from epithelial ovarian cancer (EOC) patients and healthy controls using polymerase chain reaction–restriction fragment length polymorphism. The results showed that the genotype frequency of p16 580C→T polymorphism was significantly different among histologic subtypes of EOC (P= 0.02). T allele carriers significantly reduced the risk of serous EOC; the adjusted odds ratio was 0.40 (95% CI = 0.19–0.84). There are neither association between p16 540C→G polymorphism and EOC development, progression, nor association between the haplotypes of two single nucleotide polymorphisms and the tumor development. Our results suggested that the p16 580C→T polymorphism might affect the individual susceptibility to specific subtypes of EOC. Different types of ovarian cancer might adopt distinct carcinogenetic pathways. However, this result may be further validated in a larger sample of patients.