The inhibitory effect of the two H1 antagonists clemastine and loratadine on histamine release in human skin was studied in 15 volunteers. The antihistamines and placebo were administered orally (clemastine 2 mg twice a day, loratadine 10 mg once a day) for 5 days according to a double-blind, crossover design. Clemastine caused a significant sedation in comparison with placebo, whereas there was no difference between loratadine and placebo in this respect. After 5 days’ medication, flare reaction was induced by intradermal injection of histamine and the histamine liberator compound 48/80. The antihistamine dosages were approximately equipotent and inhibited the flare response induced by histamine to about the same extent, whereas the flares induced by compound 48/80 were still more inhibited by both drugs. The results indicate that clemastine and loratadine not only inhibit histamine effects at H1 receptor level, but have additional suppressive effects, probably due to inhibition of mast cell degranulation. The simple, virtually noninvasive, in vivo technique described in this paper does not require chemical analysis of the released mediators and could be used to screen ‘mast cell stabilizing’ effects of various antihista