The objective of this study is to detect the infection of human papillomavirus (HPV) and the expression of p16(INK4a) in cervical lesions and to investigate the interaction between hrHPV and p16(INK4a) for cervical lesions and its diagnostic efficiency. hrHPV-DNA was detected by the hybrid capture II (HC-II) system. Immunochemical method was used to detect the expression of p16(INK4a), and histopathologic test was performed to identify cervical lesions. χ(2) test and Spearman's rank correlation were used for statistical analysis. Additive effects model was used to analyze the interaction. The diagnostic sensitivity, specificity, positive predictive values, negative predictive values, accuracy, and the area under the receiver operating characteristic curve were calculated with SPSS 13.0. hrHPV and p16(INK4a) positive rate increased (P < 0.05) with histopathologic diagnosis increasing. The positive rates of hrHPV and p16(INK4a) in negative or chronic inflammation were statistically lower than that in cervical intraepithelial neoplasia (CIN)1, CIN2, CIN3, and squamous-cell carcinoma (SCC) (P < 0.05), respectively. There was a positive interaction between hrHPV and p16(INK4a), relative excess risk of interaction (RERI) was 52.49, attributable proportions of interaction (API) were 72.34%, and the synergy index (S) was 3.75. The specificity and AUC of combining hrHPV with p16(INK4a) were statistically higher than hrHPV or p16(INK4a) alone (P < 0.05). hrHPV and p16(INK4a) are useful markers for the early diagnosis of cervical lesions. A positive interaction between hrHPV and p16(INK4a) is seen. The combination of hrHPV and p16(INK4a) has a higher diagnostic accuracy than hrHPV or p16(INK4a) alone in diagnosis of cervical lesions.