The authors compared US Food and Drug Administration (FDA) and 9 pharmacologically guided approaches (PGAs; simple allometry, maximum life span potential [MLP], brain weight, rule of exponent [ROE], two 2-sp methods and 3 one-sp methods) to determine the maximum recommended starting dose (MRSD) for first-in-human clinical trials in adult healthy men using 10 drugs. The ROE method as suggested by Mahmood and Balian1gave the best prediction accuracy for a pharmacokinetic (PK) parameter. Values derived from clearance were consistently better than volume of distribution (Vd)-based methods and had lower root mean square error (RMSE) values. A pictorial method evaluation chart was developed based on fold errors for simultaneous evaluation of various methods. The one-sp method (rat) and the US FDA methods gave the highest prediction accuracy and low RMSE values, and the 2-sp methods gave the least prediction accuracy with high RMSE values. The ROE method gave more consistent predictions for PK parameters than other allometric methods. Despite this, the MRSD predictions were not better than US FDA methods, probably indicating that across-species variation in clearance may be higher than variation in no observed adverse effect level (NOAEL) and that PGA methods may not be consistently better than the NOAEL based methods.