We studied the influence of AIDS restriction genes (ARGs) CCR5-Δ32, CCR2-64I, SDF1-3′A, IL10-5′A, CX3CR1-V249I, CX3CR1-T280M, and MDR1-C3435T and haplotypes of the CCR5 P1 promoter and RANTES variants -403A, In1.1C, 3′222C, and -28G among HIV-1 infected patients on highly active antiretroviral therapy (HAART) in the Multicenter AIDS Cohort Study (MACS) and the Multicenter Hemophilia Cohort Study (MHCS). Our results indicate that several ARGs also influence therapy efficacy (ie, the success in viral suppression) and subsequent progression to AIDS while on HAART. CCR5-Δ32 decreased time to viral suppression (<200 HIV RNA copies/mL, relative hazard [RH] = 1.40; P = 0.008) and was protective against AIDS (RH = 0.11; P = <0.0001), whereas the CCR5 P1 haplotype was associated with delayed viral suppression (RNA <50 copies/mL, odds ratio [OR] = 0.65; P = 0.03) and accelerated time to AIDS (RH = 2.68; P = 0.02). SDF1-3′A reduced viral suppression (OR = 0.61; P = 0.02) and accelerated AIDS (RH = 3.18; P = 0.009). Accelerated AIDS progression was also observed with the RANTES haplotype carrying RANTES-IN1.1C and RANTES-3′222C (P = 0.005 to 0.007). In contrast, the RANTES haplotype H1, which lacks suspected deleterious single-nucleotide polymorphisms, was protective against AIDS. CX3CR1-V249I seemed to accelerate viral suppression (RNA <50 copies/mL, OR = 1.27; P = 0.01). ARG influence after HAART suggests residual HIV-1 replication, and spread continues even in patients successfully suppressing detectable viral RNA.