The performance of different devices for percutaneous allergy skin testing may have statistically and clinically significant differences. We compared two multihead allergy skin testing devices: Multi-Test II (Lincoln Diagnostics, Decatur, IL) and ComforTen (Hollister-Stier Laboratories, Spokane, WA). Skin tests with glycerinated histamine (6 mg/mL base) and glycerinated saline were applied to 30 adults using Multi-Test II on the volar surface of one forearm and ComforTen on the opposite forearm. For each device, data were obtained from 150 histamine sites and 90 negative control sites. Defining a positive result using cutoff wheal sizes of either 5-mm versus 3-mm inclusive, respective results for Multi-Test II sensitivity were 97% versus 100% with specificity of 100% versus 97%, whereas corresponding ComforTen sensitivity increased from 26 to 82% with specificity of 100% versus 99%. For Multi-Test II versus ComforTen, histamine mean (SD) wheal sizes were 7.47 (1.72) mm versus 3.93 (1.59) mm (p = 0.00), mean coefficients of variation (CV) were 23.0% versus 40.5%, and pooled estimates of variance were 1.42 versus 1.29. Comparing results at different test head positions, there was no statistically significant variation in histamine wheal sizes with either device. Multi-Test II had notably lower CV, greater wheal size, and higher sensitivity but similar specificity to ComforTen. Consequently, Multi-Test II had superior performance at both 3- and 5-mm wheal cutoffs. Because ComforTen had a low sensitivity at the 3-mm and, particularly, at the 5-mm wheal cutoff, skin testing with this device might result in underdiagnosis of allergy using either cutoff.