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Impact of HIV on the health-related quality of life in youth with perinatally acquired HIV. BACKGROUND: Studies investigating health-related quality of life (HRQoL) in youth with perinatally acquired HIV (PHIV+) are scarce. This study aimed to compare HRQoL of PHIV+ to sociodemographic-matched youth not living with HIV (HIV-), Spanish general youth population, and to explore associations between sociodemographic variables, drug consumption, and HRQoL. METHODS: PHIV+ youth were randomly selected from CoRISpe database (Cohort of the Spanish Pediatric HIV Network). HRQoL was evaluated by SF-12v2. RESULTS: Thirty-nine PHIV+ youth (mean age: 23.36 years, SD = 3.83) and thirty-nine HIV- youth (mean age: 22.97 years, SD = 3.80) participated in this study. PHIV+ obtained lower scores in SF-12 physical health subscale (PCS) than HIV- (P = 0.001) and Spanish general youth population (P = 0.006). PHIV+  had lower scores on the mental health subscale (MCS) than the Spanish general youth population (P < 0.001). PHIV+  who were at school obtained better scores than those were not at school. PHIV+  youth who had used cocaine and cannabis had lower scores in MCS (P = 0.002). CONCLUSIONS: There is a need for HRQoL management in the associated medical follow-up.