The hypnotic effects of propofol, midazolam, alfentanil, and their binary and triple combinations, were studied in 130 unpremedicated patients in a randomized, double-blind fashion. The ability to open eyes on verbal command was used as an end-point. Doseresponse curves for the three drugs given separately and in combination were determined with a probit procedure and the ED50 values were compared with an isobolographic analysis. The ratios of a singledrug fractional dose (ED50 = 1.0) to a combined fractional dose (in fractions of single-drug ED50 values) indicating the degree of superadditivity (synergism) were: 1.4 (P < 0.05) for propofol-alfentanil, 1.8 (P < 0.0005) for midazolam-propofol, 2.8 (P < 0.0001) for midazolam-alfentanil, and 2.6 (P < 0.0001) for propofol-midazolam-alfentanil. The results indicate that the propofol-midazolam-alfentanil interaction produces a profound hypnotic synergism which is not significantly different from that of the binary midazolam-alfentanil combination.