In the province of Lecce (southern Italy), a higher incidence of lung cancer (LC) among men compared to regional and national data was reported. In a sub-area in the center of the province (cluster area), the incidence and mortality for LC was even higher. PROTOS is a case–control study aimed at investigating possible risk factors for LC in the province area. A total of 442 patients with LC and 1326 controls matched by sex and age living in the province of Lecce for at least 10 years were enrolled and georeferenced; they filled in a questionnaire with their personal information and exposures. For each risk factor, an Odds Ratio adjusted for all the other variables was calculated. The risk of LC increased with excessive use of alcohol in women, for those subjects with a family cancer history, for each increase in pack/year of cigarettes, for men more exposed considering the industrial district in the cluster area, and for those using pesticides in agriculture without wearing personal protective equipment. The higher incidence of adenocarcinoma in both sexes suggests that, in addition to cigarette smoking, concurrent exposures to other environmental, occupational, and life-style factors may play a role in increased cancer risk and should be more deeply explored.