Background. The safety and immunogenicity of high-dose pandemic H1N1 (pH1N1) vaccination in perinatally human immunodeficiency virus type 1 (HIV-1)-infected children, adolescents, and young adults are unknown. Methods. Two 30-g doses of 2009 Novartis pH1N1 monovalent vaccine (Fluvirin) were administered 21-28 days apart to perinatally HIV-1-infected children, adolescents, and young adults. Antibodies were measured by hemagglutination inhibition (HAI) assay at baseline, 21-28 days after first vaccination, 7-13 days after the second vaccination, and 7 months after the first vaccination. Results. Among the 155 participants, 54 were aged 4-8 years, 51 were aged 9-17 years, and 50 were aged 18-24 years. After 2 doses of Fluvirin, seroresponse (≥4-fold rise in HAI titers) was demonstrated in 79.6, 84.8, and 83 of participants in the aforementioned age groups, respectively, and seroprotection (HAI titers ≥40) was shown in 79.6, 82.6, and 85.1, respectively. Of those lacking seroresponse (n = 43) or seroprotection (n = 37) after the first vaccination, 46.5 and 40.5 achieved seroresponse or seroprotection, respectively, after the second vaccination. Among participants who lacked seroprotection at entry, a "complete response" (both seroresponse and seroprotection) after first vaccination was associated with higher baseline log10 HAI titer and non-Hispanic ethnicity. No serious vaccine-related events occurred.Conclusion.Two doses of double-strength pH1N1 vaccine are safe and immunogenic and may provide improved protection against influenza in perinatally HIV-1-infected children and youth. Clinical Trials Registration. NCT00992836. © 2012 The Author.