Persistent human papillomavirus (HPV) infection seems central to cervical carcinogenesis. Smoking is associated with cervical cancer in HPV DNA-positive women, but its association with HPV persistence is unclear, particularly with respect to human immunodeficiency virus (HIV) serostatus. The authors evaluated smoking and HPV clearance by HIV serostatus among 801 women from the HIV Epidemiology Research Study (United States, 1993-2000). Type-specific HPV duration was defined as the interval between initial MY09/11 polymerase chain reaction positivity and the first of two consecutive HPV-negative study visits. Hazard ratios adjusted for study site and risk behaviors (sexual activity or injection drug use) were estimated using Cox regression. This analysis included 522 HIV-seropositive and 279 HIV-seronegative women (median follow-up, 4.4 years). Ever smoking was associated with reduced clearance of high-risk HPV in HIV-seronegative women (hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.30, 0.88) but not in HIV-seropositive women (HR = 0.96, 95% CI: 0.65, 1.42); similar results were found for current smoking. Current smoking was not associated with clearance of any type-specific HPV in HIV-seropositive (HR = 0.99, 95% CI: 0.82, 1.20) or HIV-seronegative (HR = 0.93, 95% CI: 0.68, 1.26) women. HPV clearance did not appear to vary by amount or duration of smoking. Smoking did not modify overall clearance but was associated with lower high-risk HPV clearance in HIV-seronegative women.