Background: Whether vexing clinical decision-making, dilemmas can be partly addrssed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number, of CCL3L1, a patent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessingAIDS risk. Methods and Findings: In a prospective, single-site, ethnically-mixed cohort of 1, 1132 HIV-positive subjects, we determined the AIDS risk conveyed bythe laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1-CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and. classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markets together provided more prognostic information than either marker alone, Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART Initiation. Conclusions: The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL31-CCR5 genotypes may have utility in HIV clinical management. These findings illustrate how genomic information might be applied to achieve practical benefits of personalized medicine.