Abstract Background The health status of people with HIV (PWH) influences their health-related quality of life (HRQOL). Modifiable lifestyle factors may improve HRQOL. This study (1) explores the association between modifiable lifestyle factors (physical activity and nutrition) and HRQOL and (2) examines if these lifestyle factors moderate the association health status and HRQOL. Methods Participants included 91 community dwelling PWH (age 36–65 years) from the university lab. Participants reported mental and physical HRQOL via the Medical Outcome Study 36-Item Short-Form (SF-36). Physical activity was examined via the International Physical Activity Questionnaire and nutrition (i.e., fruit and vegetable consumption) was assessed with the By-Meal Screener. Health status was ascertained via the Veterans Aging Cohort Study (VACS) Index. Results Aim 1 analyses indicated that neither physical activity nor nutrition was related to mental HRQOL (p’s > .05). However, greater physical activity (β = .33, p < .01) and nutrition (β = .23, p = .03) were each independently related to better physical HRQOL and remained significant after accounting for co-occurring medical conditions. For aim 2, the interaction between health status and nutrition was statistically significant (β = .24, p = .02), such that the association between worse health status and worse physical HRQOL was weaker with better nutrition. There was not a statistically significant interaction between physical activity and health status on physical HRQOL (p > .05). Conclusion Physical HRQOL is related to self-reported physical activity and nutrition, with nutrition showing a moderating effect on the association between health status and physical HRQOL. Thus, future interventional studies designed to improve physical HRQOL should target both physical activity and nutrition.