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To design microneedles that minimize pain, this study tested the hypothesis that microneedles cause significantly less pain than a 26-gauge hypodermic needle, and that decreasing microneedle length and the number of microneedles reduces pain in normal human volunteers.Single microneedles with lengths ranging from 480 to 1450 μm, widths from 160 to 465 μm, thicknesses from 30 to 100 μm, and tip angles from 20 to 90 degrees; and arrays containing 5 or 50 microneedles were inserted into the volar forearms of 10 healthy, human volunteers in a double-blinded, randomized study. Visual analog scale pain scores were recorded and compared with each other and to the pain from a 26-gauge hypodermic needle.All microneedles investigated were significantly less painful than the hypodermic needle with microneedle pain scores varying from 5% to 40% of the hypodermic needle. Microneedle length had the strongest effect on pain, where a 3-fold increase in length increased the pain score by 7-fold. The number of microneedles also affected the pain score, where a 10-fold increase in the number of microneedles increased pain just over 2-fold. Microneedle tip angle, thickness, and width did not significantly influence pain.Microneedles are significantly less painful than a 26-gauge hypodermic needle over the range of dimensions investigated. Decreasing microneedle length and number of microneedles reduces pain.