In a cohort study, Palella and colleagues (1) investigated the utility of HIV drug resistance testing by analyzing patient survival as a function of whether a physician had ordered either a genotype or phenotype resistance test (GPT). Their report is instructive and highlights the advantages and limitations of observational research versus randomized clinical trials. The HOPS (HIV Outpatient Study) is a Centers for Disease Control and Prevention–supported study in which data have been collected prospectively from 10 U.S. sites since 1993. Mostly cared for in university or private practice clinics, participants are disproportionately white, male, engaged in homosexual behavior, and privately insured. Palella and colleagues identified 3 subgroups: patients naive to antiretroviral therapy; those currently receiving therapy; and those who had received all classes of antiretroviral drugs available from January 1999 to December 2005, but in whom therapy failed. They measured the use of GPT, as evidenced by the medical record, and evaluated its association with mortality in the overall cohort and in the 3 subgroups. After adjusting statistically for baseline between-group differences in factors that were expected to contribute to lower mortality (including higher CD4 cell counts, white race, private insurance, and no injection drug use), they found that GPT was associated with an overall survival advantage. The advantage was most evident in the subgroup receiving antiretroviral therapy at baseline. Testing did not have a significant benefit in those who were treatment-naive at baseline. Palella and colleagues did not compare the actual results of GPT or any resulting adjustment in treatment regimens, an analysis that the authors stated might be instructive. They conclude that ordering GPT in HIV care is associated with decreased mortality, particularly in patients already receiving treatment at the time of testing.