Variability in production predictions caused by geologic heterogeneity and uncertainty was examined with a new method. The experimental design maximized the information derived from the flow simulation of various geologic models. Empirical response surface models were fit to simulation results to assess the consequences of varying several geologic factors. Posterior distributions of geologic parameters were estimated from flow responses. Improvements in the accuracy of the reservoir model were quantified by computing changes in factor uncertainties resulting from response measurements. Monte Carlo simulations with prior and posterior factor distributions illustrate uncertainty reduction. This approach can be used for model comparison, sensitivity analysis, and estimation of probability distributions of geologic model parameters.