The authors studied the interaction between sevoflurane and remifentanil on bispectral index (BIS), state entropy (SE), response entropy (RE), Composite Variability Index, and Surgical Pleth Index, by using a response surface methodology. The authors also studied the influence of stimulation on this interaction. Forty patients received combined concentrations of remifentanil (0 to 12 ng/ml) and sevoflurane (0.5 to 3.5 vol%) according to a crisscross design (160 concentration pairs). During pseudo-steady-state anesthesia, the pharmacodynamic measures were obtained before and after a series of noxious and nonnoxious stimulations. For the "prestimulation" and "poststimulation" BIS, SE, RE, Composite Variability Index, and Surgical Pleth Index, interaction models were applied to find the best fit, by using NONMEM 7.2.0. (Icon Development Solutions, Hanover, MD). The authors found an additive interaction between sevoflurane and remifentanil on BIS, SE, and RE. For Composite Variability Index, a moderate synergism was found. The comparison of pre- and poststimulation data revealed a shift of C50SEVO for BIS, SE, and RE, with a consistent increase of 0.3 vol%. The Surgical Pleth Index data did not result in plausible parameter estimates, neither before nor after stimulation. By combining pre- and poststimulation data, interaction models for BIS, SE, and RE demonstrate a consistent influence of "stimulation" on the pharmacodynamic relationship between sevoflurane and remifentanil. Significant population variability exists for Composite Variability Index and Surgical Pleth Index.