BACKGROUND Neuropeptides appear to participate in the pathogenesis of chronic urticaria. The purpose of this study was to investigate the cutaneous responses to substance P (SP) and calcitonin gene-related peptide (CGRP) in delayed pressure urticaria patients (DPUpt) and chronic idiopathic urticaria patients (CIUpt) compared to healthy adults (HA), and also to evaluate the effect of H1-antagonists on these responses. METHODS Wheal (W) and flare (F) reactions to intradermally (ID) injected SP, CGRP, histamine (H), and diluent controls were evaluated in nine CIUpt, nine DPUpt, and nine HA at 3, 7, 15, 30, 60, and 120 min after injection. Maximal W and F, area under curve (AUC), and time of W and F disappearance were calculated at baseline and 4 h after a single dose of 20 mg cetirizine (Ce), 4 mg dimethindene (Di), or placebo (P), in a double-blind, placebo-controlled (DBPC), crossover, randomized study. RESULTS CIUpt exhibited enhanced and longer lasting W reactions to SP and CGRP (AUC: P<0.05) than HA; SP- and CGRP-induced F (at maximal concentration) were larger and longer lasting in CIUpt than in HA (P<0.003 and P = 0.004, respectively). In the DPU group, SP-induced W and F responses were intermediate in magnitude compared to CIUpt and HA. In HA, SP-induced flares were significantly suppressed only by Ce (P<0.020), while both Ce and Di affected SP-induced W and F in the two patient groups (P<0.05). CGRP-induced flare inhibition by the two H1-antagonists was also greater in the urticaria patient groups than in HA. CONCLUSIONS CIUpt and, to a lesser extent, DPUpt showed enhanced SP- and CGRP-induced W and F reactions. CGRP elicited an immediate W and F response, followed by prolonged erythema. H1-antagonists partially affected W and F reactions to SP and only the F response induced by CGRP; this effect was more pronounced in the urticaria patient groups than in HA. Overall, W and F cutaneous responses to SP were suppressed to a greater extent by Ce than Di.