Objective: To evaluate the correlation between host genetic profiles and virological and immunological outcomes among HIV-l-seropositive participants from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort. Methods: HLA class I and chemokine coreceptor (CCR) alleles and haplotypes were resolved in 227 HIV-1 -seropositive adolescents (ages 13-18 years; 75% females; 71% African-Americans) and 183 HIV-seronegative individuals, with quarterly follow-up visits between 1996 and 2000. Each HLA and CCR variant with consistent risk and protective effect on HIV-1 pathogenesis was assigned a score of -1 and +1, respectively. All individual markers and genetic scores were analyzed in relation to plasma viral load (VL) and CD4 T lymphocytes during a 6-12-month interval when no antiretroviral therapy was taken. Results: HLA-B* 57 alone was a strong predictor of VL (P < 0.0001), but composite genetic profiles found in over 50% of patients consistently outperformed the individual component markers in multivariable analyses with or without adjustment for gender, race, age, and membership of clinical patient groups. Adolescents (n = 37) with a favorable combination of VL (< 1000 copies/ml) and CD4 T cell counts (> 450 × 106 cells/I) consistently had more positive (+1 to +2) than negative (-1 to -4) HLA and CCR scores compared with those (n = 56) with an unfavorable combination (VL > 16 000 copies/ml and CD4 cells < 450 × 106 cells/I) or the remainder (n = 134) of the cohort (overall P < 0.0001). Conclusion: A generalizable genetic scoring algorithm based on seven HLA class I and CCR markers is highly predictive of viremia and immunodeficiency in HIV-1-infected adolescents. © 2002 Lippincott Williams & Wilkins.