Angiotensin receptor blockers (ARBs) have multiple effects that may contribute to their efficacy on renal/cardiovascular outcomes. We developed and validated a risk score that incorporated short-term changes in multiple risk markers to predict the ARB effect on renal/cardiovascular outcomes. The score was used to predict renal/cardiovascular risk at baseline and at month 6 in the ARB treatment arm of the Reduction of Endpoints in NIDDM (noninsulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial. The net risk difference at these time points indicated the estimated long-term renal/cardiovascular treatment effect. Predicted relative risk reductions (RRRs) based on multiple markers were close to observed RRRs for renal (RRR(predicted): 30.1% vs. RRR(observed): 21.8%; P = 0.44) and cardiovascular outcomes (RRR(predicted): 9.4% vs. RRR(observed): 9.2%; P = 0.98), in addition to being markedly more accurate than predicted RRRs based on changes in single markers. The score was validated in an independent ARB trial. Predictions of long-term renal/cardiovascular ARB effects are more accurate when considering short-term changes in multiple risk markers, challenging the use of single markers to establish drug efficacy.