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Physical urticaria (PU) includes a heterogeneous group of urticarias whose etiopathogenic aspects are still obscure and whose therapeutical management is often difficult. We have previously demonstrated the efficacy of a sequential treatment with nimesulide, a unique nonsteroidal anti-inflammatory drug, and ketotifen in various forms of PU.The expression of some inflammatory parameters was evaluated in 10 patients affected with some forms of PU. In particular, serum levels of interleukin (IL)-4, IL-1β, tumor necrosis factor (TNF)-α, adhesion molecules (sELAM, sICAM-1 and sVCAM), soluble receptors (sIL-2R, sCD30, sCD23) and IgE were assessed. Moreover, the cutaneous expression of IL-1β, TNF-α and ICAM-1 was studied on biopsy specimens taken from nonlesional skin of patients. The same parameters were further evaluated in both skin and serum following treatment with nimesulide and ketotifen, in order to better understand the possible effects of these agents on the inflammatory network of PU.Before therapy we could detect significantly higher serum levels of IL-1β and TNF-α (P < 0.001) and of circulating adhesion molecules in comparison with controls (sELAM, sICAM:P < 0.001; sVCAM:P < 0.02); after treatment, a significant reduction of each was observed (P < 0.05). Simultaneously, a high expression of IL-1β, TNF-α and ICAM-1 was detected in all skin specimens at the baseline, with a relevant decrease following therapy.These results confirm the therapeutical value of treatment with nimesulide and ketotifen in PU and suggest that these agents are able to reduce the release and the expression of some inflammatory molecules that are up-regulated in PU.