BACKGROUND The most intriguing function attributed to interleukin-31 (IL-31) is its ability to induce pruritus in pathologic conditions, such as atopic dermatitis (AD). As of today, this feature of IL-31 was tested in vivo only in animal models. METHODS Ten patients with AD and 10 healthy controls were challenged with IL-31 and NaCl (negative control) by skin prick testing. Twenty additional healthy controls were subjected to skin prick testing with histamine. Itch and local inflammatory responses of the skin were assessed for up to 72 h. RESULTS All of the histamine-challenged subjects developed immediate pruritus (i.e. within the first 5 min). In contrast, only one IL-31- and two of the NaCl-challenged subjects reported immediate itch at the provocation site (short lasting, for 2-6 min). Nine subjects (five patients with AD) reported late itch responses to IL-31 challenges with a mean delay of 143 min. No subject reported late itch responses to histamine or NaCl testing. There was no significant difference in IL-31-induced itch start time, duration and intensity between patients with AD and healthy volunteers. CONCLUSIONS IL-31 does not induce immediate itch responses in humans. The late onset of IL-31-induced itch supports the notion that IL-31 exerts its pruritic effect indirectly via keratinocytes and secondary mediators, rather than through its receptors on cutaneous nerves.