BACKGROUND: Lung cancer is the leading cause of cancer death in Taiwan, and the paucity of dependable risk markers has impeded the early management of lung cancer. An association of human papillomavirus (HPV) 16/18 infection with lung cancer among nonsmoking Taiwanese women was revealed in our previous study. METHODS: Nested PCR was employed to detect HPV 16/18 DNA in the blood circulation of 149 lung cancer patients and 174 noncancer controls. In addition, correlation of prevalence of HPV DNA between the blood circulation and lung tumor tissue was compared from 70 sets of paired tumor tissues and peripheral blood samples available. RESULTS: The results showed that the prevalence rate of HPV 16/18 in the blood circulation of lung cancer cases was significantly higher than that of noncancer controls (47.7% vs. 12.6% for HPV 16, P < 0.0001; 30.9% vs. 5.2% for HPV 18, P < 0.0001). A significantly higher HPV 16 prevalence was detected in female lung cancer patients than that of male (57.6% vs. 41.1%, P = 0.048), as well as in cases with tumor Stages III/IV than those with tumor Stages I/II (54.6% vs. 29.3%, P = 0.006). After adjusting the effects of age, gender, and smoking status, a 6.5-fold greater risk of lung cancer was demonstrated for those subjects with HPV Type 16 positive (95% CI 3.7-11.3, P < 0.0001), a 9.2-fold for HPV Type 18 positive (95% CI 4.2-20.2, P < 0.0001), and a 75.7-fold greatest risk for those with both HPV Type 16 and 18 positive (95% CI 9.8-582.1, P < 0.0001). CONCLUSIONS: These results suggested that the presence of HPV DNA in the blood circulation may serve as a feasible risk marker of lung cancer. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11191