Children living with perinatal HIV illness (PHIV+) disproportionately reside in disadvantaged neighborhoods and contend with persistent mental health challenges. This study examined the influences of disadvantaged residential neighborhood on anxiety and depression, and potential resources that buffer against internalizing problems when youths were exposed to neighborhood stressors. Multilevel analysis of 196 PHIV+ and 129 perinatally HIV-exposed but uninfected youth (PHIV-) in New York City found that higher exposure to neighborhood disorder was associated with higher levels of depression and anxiety for PHIV+ and PHIV- youths. Stressful events unrelated to residential neighborhoods significantly mediated the relationship between neighborhood disorder and anxiety and depression. Social problem solving and religiosity did not moderate the relationship between neighborhood disorder and internalizing problems. Our findings highlighted that interventions that attenuate the negative effects of stressful life events were equally critical in addressing the broader impact of disadvantaged neighborhoods on the mental health of youth affected by HIV. (Contains 4 tables.)