Background: In June 2004, the Aquitaine Regional Health Agency (CIRE) was contacted by an occupational physician concerned about the high number of cancer cases—particularly lung cancer—among employees of a Bordeaux-based bus company over the past seven years. In collaboration with occupational health services and the environmental health department of the DDAS, the Cire conducted an investigation to verify the possibility of an excess of cancer cases and the existence of a common environmental and/or occupational risk factor that could explain this cluster of cases. Method: The approach adopted is based on the methodological guide developed by the French Institute for Public Health Surveillance for the assessment and management of spatio-temporal clusters of non-infectious diseases. This pragmatic approach conducts the investigation according to a decision tree comprising several steps. Based on the collected health and environmental data, a decision is then made on whether to continue the investigation. Results: A total of 6 cases of primary lung cancer of the same histological type (adenocarcinoma) were identified among the staff of this company, which has 293 employees. Among these cases, 4 were bus drivers. All cases of lung cancer involved significant current or past tobacco use, with an average of more than 20 cigarettes per day over an average duration of 31 years. Although the median age at diagnosis was lower than that found in the general population (52 years versus 67 years), the calculation of the standardized incidence ratio (SIR) did not reveal an excess incidence of cancer, and more specifically of lung cancer, in this population of workers compared to national benchmarks. Environmental investigations revealed that employees of this company were exposed to a generally unfavorable work environment, particularly with regard to exposure to air pollution. This exposure is most certainly, as confirmed by the literature, higher among bus drivers. Nevertheless, the attributable share of environmental and occupational exposures in the occurrence of lung cancer remains unquestionably very modest compared to that linked to smoking. Discussion - conclusion: since the assessment of drivers’ exposure to air pollution, and more specifically to diesel particulate matter, is insufficiently documented, additional air samples could be collected. Furthermore, surveillance of all new cancer cases must continue, ensuring that socio-demographic data—essential for conducting epidemiological studies—is thoroughly collected. Finally, since smoking is the most obvious risk factor, it would certainly be advisable to consider implementing appropriate prevention measures for the company’s employees.