The risk of clinical progression for human immunodeficiency virus (HIV)-infected persons receiving treatment with highly active antiretroviral therapy (HAART) is poorly defined. From an inception cohort of 8457 HIV-infected persons, 2027 patients who started HAART during prospective follow-up were examined. Results were validated in another 2 groups of patients (n=1946 and n=1442). In total, 200 patients (9.9%) experienced clinical progression during 5177 person-years (incidence, 3.9/100 years). The most recently measured CD4 cell count, virus load, and hemoglobin level all were independently related to the risk of clinical progression, as was a diagnosis of severe AIDS before the start of HAART. On the basis of these findings, a scoring system was derived (range, 0-17). A single unit increase in the score was associated with a 38% increased risk of clinical progression (relative hazard, 1.38; 95% confidence interval, 1.33-1.43; P<.0001). The scoring system was validated with remarkably good agreement in the 2 other cohorts. This system can be used in patient and resource management.