Given the potential differences in performance of skin test devices, the purpose of this study was to prospectively assess the performance of two single-headed and two multiheaded devices for allergy skin testing in terms of wheal size, sensitivity, specificity, intradevice variability, and pain level. Two single-headed devices (Greer Pick, Duotip-Test) and two multiheaded devices (Multi-Test II, OMNI) were tested in 15 subjects in a prospective partially blind fashion looking at wheal reactions and pain using histamine and glycerol-saline on the arms and back. Differences among devices in wheal size and pain were noted. Sensitivity, specificity, and intradevice variability were calculated. Differences between corner and interior heads in multiheaded devices were analyzed. No significant differences were observed in wheal size between Greer Pick (7.1+/-1.4 mm) and Duotip-Test (7.2+/-1.6 mm). Multiheaded devices were significantly different in wheal size compared with each other and to the single-headed devices (Multi-Test II, 5.4+/-1.7 mm; OMNI, 3.3+/-1.2 mm). Single-headed devices were more sensitive (100% each, 95% CI of 92-100%) than the multiheaded devices. Multi-Test II was significantly more sensitive (83%, 95% CI of 78-87%) than OMNI (57%, 95% CI of 51-62%). There was significant intradevice variability for the multiheaded devices with corner heads being significantly more sensitive than interior heads. Specificities for all devices were equally good (-97%). Pain was greater for multiheaded devices than single-headed devices but was generally mild. In conclusion, this study supports the idea that single-headed devices may be more sensitive and consistent than multiheaded devices. Multi-Test II is more sensitive than OMNI. In multiheaded devices, corner heads are more sensitive than interior heads.