Neutral endopeptidase (NEP) is an ubiquitous enzyme that inactivates numerous endogenous peptides in the brain, kidney, and lung in vivo. The origin of the circulating soluble form and its determinants are largely unknown. The relationships of smoking habits and alcohol consumption to serum NEP activity have been explored in a longitudinal epidemiological study conducted in 204 Lorraine coal miners. At both surveys, 4 years apart, NEP activity was significantly related to alcohol consumption (in grams/day) reported by questionnaire, with correlation coefficients of 0.26 (p = 0.001) in 1990 and 0.23 (p = 0.001) in 1994. The correlations of gamma-glutamyltransferase to NEP activity were even stronger with correlation coefficients of 0.71 (p = 0.0001) in 1990 and 0.79 (p = 0.0001) in 1994. Longitudinally, the change in NEP activity between the first and the second surveys was significantly correlated with change in alcohol consumption (r = to 0.18, p = 0.02) and with change in gamma-glutamyltransferase level (r = 0.60, p = 0.0001). Serum NEP activity was unrelated to smoking habits. Results support the hypothesis of a causal role of alcohol on serum NEP activity.