Objective: This article investigates whether differences in utility scores based on the EQ-5D and the SF-6D have impact on the incremental cost-utility ratios in five distinct patient groups. Methods: We used five empirical data sets of trial-based cost-utility studies that included patients with different disease conditions and severity (musculoskeletal disease, cardiovascular pulmonary disease, and psychological disorders) to calculate differences in quality-adjusted life-years (QALYs) based on EQ-5D and SF-6D utility scores. We compared incremental QALYs, incremental cost-utility ratios, and the probability that the incremental cost-utility ratio was acceptable within and across the data sets. Results: We observed small differences in incremental QALYs, but large differences in the incremental cost-utility ratios and in the probability that these ratios were acceptable at a given threshold, in the majority of the presented cost-utility analyses. More specifically, in the patient groups with relatively mild health conditions the probability of acceptance of the incremental cost-utility ratio was considerably larger when using the EQ-5D to estimate utility. While in the patient groups with worse health conditions the probability of acceptance of the incremental cost-utility ratio was considerably larger when using the SF-6D to estimate utility. Conclusions: Much of the appeal in using QALYs as measure of effectiveness in economic evaluations is in the comparability across conditions and interventions. The incomparability of the results of cost-utility analyses using different instruments to estimate a single index value for health severely undermines this aspect and reduces the credibility of the use of incremental cost-utility ratios for decision-making.