To explore the association between the anorexigenic effects of nicotine and the orexigenic properties of ghrelin, plasma total ghrelin levels were measured in nonsmokers and habitual smokers before and after short-term exposure to cigarette smoke. Thirty-one male smokers and 23 nonsmoking volunteers were matched for age and body mass index. After an overnight fast and abstinence from smoking, they all smoked 2 cigarettes consecutively (same brand, rate of inhalation, and duration of smoking). Total ghrelin concentrations were measured by radioimmunoassay before smoking (baseline), immediately afterward, and 30, 60, and 90 minutes after the second cigarette. Baseline ghrelin levels were not different between smokers and nonsmokers. Smoking did not have an immediate influence on ghrelin concentrations in smokers (analysis of variance for repeated measurements, P=0.74), whereas there was a progressive decline in nonsmokers, reaching statistical significance at 30 minutes (P=.04) and a nadir at 60 minutes (P=.04) after smoking. Moreover, the area under the curve for the changes of ghrelin over time after smoking was lower in nonsmokers than in smokers (-287.2+/-167.1 vs 29.2+/-125.3 ng.min/L, P=.03). In conclusion, fasting plasma total ghrelin concentrations are not different between male smokers and nonsmokers. Smoking does not provoke any short-term change in ghrelin levels in smokers, but induces a decline in nonsmokers. If the anorectic effect of smoking is ghrelin induced, this effect may be present only in people not habituated to smoke exposure. In habitual smokers, ghrelin suppression by short-term smoking could be blunted as a result of desensitization due to prolonged nicotine exposure.