Propofol is frequently used for sedation, induction, and maintenance of anesthesia. It is, however, associated with pain on injection. Propofol-Lipuro has an oil phase that allows a larger proportion of propofol to be dissolved in it and, thereby, apparently reduces pain. However, studies investigating this have had methodological limitations. We devised a randomized, double-blind, crossover study comparing pain on injection between two preparations of propofol, Diprivan and Propofol-Lipuro, in subanesthetic doses. Sixty healthy patients received the drugs in random order via the same injection site separated by 10 min and a 0.9% saline flush. Pain was assessed using a verbal rating score (VRS) during and at 1-min time points after injection. Differences in VRS between the two propofol preparations at different time points in each patient were analyzed. In patients who were given Diprivan first followed by Propofol-Lipuro (group D-P), pain was significantly reduced with Propofol-Lipuro compared with Diprivan during initial injection (median difference in VRS = 2 [interquartile range 0-2], P = 0.002) and at 1 min (3 [0-4], P < 0.001). In patients who were given Propofol-Lipuro first followed by Diprivan (group P-D), no significant differences in VRS were shown. Propofol-Lipuro is associated with reduced injection pain compared with Diprivan and also seems to attenuate subsequent injection pain of Diprivan when administered first. The mechanism is unknown, but may be related to a reduction in the concentration of propofol in the aqueous phase.