The association between smoking and HIV disease progression has been examined in several studies; however, findings have been inconsistent. We examined the effect of recent cigarette smoking on CD4(+) T cell count/µl (CD4 count) and HIV RNA concentration (HIV viral load (VL)) among two HIV-infected cohorts with alcohol problems in Massachusetts in the periods 1997-2001 and 2001-2006 using a prospective cohort design and linear mixed models. Smoking groups were defined as: minimal or non-smokers, light smokers, moderate smokers, and heavy smokers. Age, alcohol use, injection drug use, depressive symptoms, gender, annual income, and antiretroviral therapy adherence were considered as potential confounders. Among 462 subjects, no significant differences in CD4 count or VL were found between smoking groups. Using minimal or non-smokers as the reference group, the adjusted mean differences in CD4 count were: 8.2 (95% confidence interval (CI): -17.4, 33.8) for heavy smokers; -0.1 (95% CI: -25.4, 5.1) for moderate smokers; and -2.6 (95% CI: -28.3, 3.0) for light smokers. For log10 VL, the adjusted differences were: 0.03 (95% CI: -0.12, 0.17) for heavy smokers; -0.06 (95% CI: -0.20, 0.08) for moderate smokers; and 0.14 (95% CI -0.01, 0.28) for light smokers. This study did not find an association between smoking cigarettes and HIV disease progression as measured by CD4 cell count and VL.