When delivered to the oral mucosa, a variety of naturally occurring chemicals such as capsaicin from red chili peppers, piperine from black pepper, and nicotine from tobacco, cause a diffuse burning sensation often referred to as irritation. The burning sensation evoked by capsaicin increases when delivered repeatedly at 1 min intervals (sensitization), but then decreases markedly following a 10 min rest period (self-desensitization). It is also interesting that following desensitization by capsaicin, irritant sensations evoked by other chemicals are also reduced (cross-desensitization), suggesting that oral irritation from some agents may be mediated by a population of capsaicin-sensitive trigeminal polymodal nociceptors. Although nicotine is a major component in tobacco smoke, little is known about its sensory properties. Accordingly, a study of the oral irritant effects of nicotine as compared with capsaicin was initiated. Whereas capsaicin (0.5 or 3 ppm; repeated at 1 min intervals over 10 min) evoked significantly stronger sensations (sensitization), there was a significant decrement in sensations to repeated application of nicotine (0.1%). After the subjects had received either repeated capsaicin or nicotine on one side of the tongue, a rest period ensued followed by a bilateral application of either capsaicin or nicotine. Subjects were, then, asked to choose which side yielded a stronger sensation (two-alternative forced choice). Following capsaicin pretreatment, all 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 was reported to evoke a significantly weaker sensation on the side of the tongue pretreated with capsaicin (cross-desensitization). In contrast, equal numbers of subjects reported capsaicin to evoke a stronger sensation on either the nicotine-pretreated side or the untreated 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.