We aimed to examine if smoking is an independent predictor of oral candidiasis (OC) among HIV-1 infected persons.The cross-sectional part of this study evaluated 631 adult dentate HIV-1 seropositive persons examined for OC from 1995-2000 at the University of North Carolina Hospitals in Chapel Hill, NC. In the second part, from the above sample, a total of 283 individuals who were free of HIV-associated oral diseases at baseline were followed up for 2 years to assess incident OC events. Data collected from medical record review, interview questionnaires, and clinical examinations were analyzed using chi-squared tests and t-tests. Logistic regression models were developed for prevalent OC employing the likelihood ratio test, whereas Poisson regression models were developed for assessing cumulative incidence of OC. These models included a variety of independent variables to adjust for confounding.Thirteen percent of participants had OC only; 4.6% had OC with Oral Hairy Leukoplakia; and 69.7% had neither. Smoking was associated with OC in all models [prevalent OC - current smokers: logistic regression - Odd ratio (95% CI) = 2.5 (1.3, 4.8); Incident OC - current smokers: Poisson regression (main effects model) - Incidence rate ratio (95% CI) = 1.9 (1.1, 3.8)]. Other Poisson regression models suggested evidence for effect modification between CD4 cell count and incident OC by smoking.Smoking is an independent risk factor for the development of OC in HIV-1 infected persons, and the risk of OC is modified by CD4 cell count which measures strength of the immune system.