Side effects from antiretroviral therapy (ART) for HIV disease can deter treatment, impact quality of life, and impede medication adherence. Individual differences in neuroticism may account for variations in the experience of side effects and perceptions of health status. Cross-sectional assessments were conducted with 258 HIV-infected participants with confirmed HIV infection and current ART regimen. Structural equation modeling (SEM) was used to evaluate a model of self-reported ART side effect frequency and severity and perceived health status, as related to symptoms of neuroticism. Symptoms of neuroticism were associated with greater reports of ART side effects and poorer perceived health but unrelated to reported CD4 count and viral load. A structural model was supported in which greater symptoms of neuroticism are linked to poorer perceived health through greater side effect frequency and severity. Individual differences in symptoms of neuroticism can explain variations in side effect reporting and consequential impairments in perceived health in the context of HIV treatment. Identification and intervention with individuals high in symptoms of neuroticism may be warranted to alleviate side effect-related concerns and maximize treatment benefit.