Many patients infected with HIV do not achieve or maintain virologic suppression below levels of detection while on potent combination antiretroviral therapy. The likelihood of emergence of incident mutations conferring reduced antiretroviral drug susceptibility was estimated among patients maintained on a stable regimen with ongoing detectable plasma HIV RNA levels. Ninety-eight HIV-infected patients were identified who had 2 genotypic antiretroviral resistance tests available. Poisson log-linear regression models were used to identify predictors and estimate incidence rates of number of acquired antiretroviral drug resistance mutations per person-year. At the 1st resistance test, 88% of patients had evidence of at least 1 mutation. Sixty percent of patients acquired at least 1 new mutation during a median of 9.3 months between consecutive resistance tests, with an incidence rate of 1.61 acquired mutations per person-year (95% CI: 1.36-1.90). Predictors of resistance evolution included average plasma HIV RNA level, HIV RNA slope, and number of mutations detected at the 1st resistance test. The likelihood of acquiring drug resistance mutations while remaining on potent combination antiretroviral therapy that does not confer complete suppression of HIV replication is relatively low and depends on the level of viral replication and prior resistance.