Psychophysical methods were used to assess changes in the intensity of irritant sensations elicited by repeated application of capsaicin and nicotine delivered unilaterally to the tongue of human subjects. Whereas capsaicin (0.5 or 3 p.p.m.; repeated at 1 min intervals over 10 min) evoked progressively stronger ratings of irritation (sensitization), there was a significant decrement in irritation ratings (desensitization) to repeated application of nicotine (0.1%). A two-alternative forced-choice (2-AFC) procedure was additionally used to test for self- and cross-desensitization. After the subjects had received either repeated capsaicin or nicotine, a rest period ensued followed by the 2-AFC procedure. Either capsaicin or nicotine was delivered bilaterally to the tongue and subjects were asked to choose which side yielded a stronger sensation. Following capsaicin pretreatment, subjects reported that capsaicin evoked a stronger sensation on the previously untreated side (capsaicin self-desensitization). Similar self-desensitization was observed with nicotine. Furthermore, nicotine evoked a significantly weaker sensation on the side of the tongue pretreated with capsaicin (cross-desensitization). In contrast, capsaicin did not consistently evoke a weaker sensation on the nicotine-pretreated side, indicating an absence of cross-desensitization. These results are discussed in terms of physiological mechanisms that might underlie the contrasting sensory effects of nicotine versus capsaicin.