We conducted two studies to determine whether the minimum clinically significant difference in the visual analog scale (VAS) for nearly simultaneous and brief-interval serial assessments of pain is less than that for pain assessment at 20- to 30-minute intervals, using a 10-cm VAS. The first study was a blinded, randomized, placebo-controlled paired trial comparing the pain of intravenous cannulation in both hands (20-minute application of a eutectic mixture of local anesthetics v placebo) of study subjects. The second study was a non-blinded, randomized, paired trial of different treatments for jellyfish stings. In the first study, 37 of 40 subjects indicated that one hand experienced more pain than the other. Eleven of these 37 subjects (30%) indicated differences in VAS values of 1.0 cm or less, with a minimum value of 0.5 cm. In the second study, for all the VAS-based pain comparisons, VAS differences of ≤0.5 cm (other than zero) occurred 183 times, and in 171 of these instances (93%) subjects were able to recognize that there was a difference. On the basis of these findings, the minimum clinically significant VAS difference for paired comparisons that are simultaneous or occur within 5 minutes of each other is about 0.5 cm or less. This value is less than the 1.3-cm value determined for serial 20- to 30-minute pain comparisons. It is likely that other types of pain comparisons may have different minimum clinically significant VAS differences.