Abstract Background: The influence of smoking on the natural history of HPV infection in men is not well understood. Smoking could influence the incidence and persistence of HPV infections by suppressing local immune function, increased cellular proliferation, upregulated proinflammatory factors, or induced host DNA damage resulting in increased susceptibility to infection. The purpose of this analysis is to assess prevalent HPV infections by smoking status in men, and to determine baseline risk of HPV infection associated with smoking. Methods: The HPV in Men (HIM) study is a multinational prospective study of the natural history of HPV infections in men. Samples from the coronal sulcus, glans penis, shaft, and scrotum were combined for HPV DNA testing. Multivariable logistic regression was used to assess the association between smoking and any-, oncogenic-, and nononcogenic HPV infections. Results: Our analyses revealed that current smoking was associated with an increased risk of any HPV infection (OR = 1.19; 95% CI: 1.01–1.41) and oncogenic HPV infection (OR = 1.24; 95% CI: 1.05–1.47). However, the association between smoking and any HPV infection (OR = 1.35; 95% CI: 1.05–1.73) and oncogenic HPV infection (OR = 1.46; 95% CI: 1.11–1.92) was only evident among men reporting fewer lifetime sexual partners. Discussion: These results suggest that current smokers with the fewest number of sexual partners are associated with an increased risk for oncogenic HPV infection. Impact: The relationship between smoking and HPV infection remains understudied in men; these data shed new light on the interplay between smoking, sexual activity, and risk of HPV infection. Cancer Epidemiol Biomarkers Prev; 21(1); 102–10. ©2011 AACR.