OBJECTIVES: To derive and validate a clinically applicable prognostic score for predicting short-term disease progression in HIV-infected patients taking combination antiretroviral therapy (cART). DESIGN AND METHODS: Poisson regression was used to identify prognostic markers for new AIDS/death in patients taking cART. A score was derived for 4169 patients from EuroSIDA and validated on 5150 patients from the Swiss HIV Cohort Study (SHCS). RESULTS: In EuroSIDA, 658 events occurred during 22 321 person-years of follow-up: an incidence rate of 3.0/100 person-years of follow-up [95% confidence interval (CI), 2.7-3.3]. Current levels of viral load, CD4 cell count, CD4 cell slope, anaemia, and body mass index all independently predicted new AIDS/death, as did age, exposure group, a prior AIDS diagnosis, prior antiretroviral treatment and stopping all antiretroviral drugs. The EuroSIDA risk-score was divided into four strata; a patient in the lowest strata would have predicted chance of new AIDS/death of 1 in 801, 1 in 401 and 1 in 201 within the next 3, 6 or 12 months, respectively. The corresponding figures for the highest strata were 1 in 17, 1 in 9 and 1 in 5, respectively. A single-unit increase in the risk-score was associated with a 2.70 times higher incidence of clinical progression (95% CI, 2.56-2.84) in EuroSIDA and 2.88 (95% CI, 2.75-3.02) in SHCS. CONCLUSIONS: A clinically relevant prognostic score was derived in EuroSIDA and validated within the SHCS, with good agreement. The EuroSIDA risk-score will be made available publicly via an interface that will perform all calculations for the individual.