Persons living with HIV/AIDS who are current smokers are more likely to develop disease-related adverse health outcomes compared to nonsmokers with HIV/AIDS. However, the impact of smoking cessation on health outcomes such as symptom status and health-related quality of life (HRQOL) has not yet been assessed within this population. This study examined the effects of changes in smoking status on HIV-related symptom burden and health-related quality of life outcomes in a multiethnic, low-income population of persons living with HIV/AIDS. Patients (n = 95) from a large, inner city HIV/AIDS clinic were enrolled in a smoking cessation trial providing nicotine replacement therapy, counseling, and self-help written materials. Biochemically verified smoking status, length of smoking abstinence, HIV-related symptom burden, and HRQOL were assessed approximately 3-months posttrial enrollment. A series of multiple linear regression models was performed to assess the associations between the smoking status variables and the health outcomes at follow-up while controlling for baseline levels. Length of smoking abstinence was significantly associated (p = 0.02) with HIV-related symptom burden. Specifically, increasing number of consecutive days of smoking abstinence during the 3-month follow-up period was associated with lower levels of HIV-related symptom burden at the time of follow-up. However, 24-hour smoking prevalence was not significantly (p > 0.05) associated with changes in either HIV-related symptom burden or HRQOL. These findings suggest that smoking cessation can significantly improve symptom burden for individuals living with HIV/AIDS. Moreover, these benefits are observable as early as 3 months after quitting and are positively correlated with the length of abstinence.