The objective of this study was to assess the relative performances of concentration-controlled trial (CCT) and dose-controlled clinical trial (DCT) designs with varying (i) interindividual variability (IIV) in clearance (CL), (ii) relative clinical importance of rejection and infection episodes, (iii) parameter values for the concentration-effect relationships, (iv) interindividual covariance between exposure and effect relationships, and (v) nonlinearity of the concentration-effect relationship. Different scenarios were simulated and analyzed for DCT and CCT designs, and these were compared with respect to bias, prediction, and power. The DCT design showed superiority across all the scenarios studied, with regard to precision and bias in parameter estimates, precision and bias in the estimate of optimal exposure, and bias in prediction of the therapeutic benefit at estimated optimal exposure. However, when a pharmacokinetic-pharmacodynamic (PKPD) covariance in the parameters was considered, either the variance-equivalent concentration-controlled trial (VCCT) or the DCT was the more useful design. Across a number of scenarios, the DCT design is the more informative one. © 2009 American Society for Clinical Pharmacology and Therapeutics.