In 2003, a cluster of renal cell carcinoma (RCC) cases was reported among men working at a French chemical plant using a proprietary process to produce vitamin A. The 10 index cases yielded a standardised incidence ratio of 13.1 for 1994-2002. Nine of these 10 cases were diagnosed by a plant-specific abdominal ultrasonography screening programme that targeted exposure to an intermediate chemical, 4-chloro-1,1-dimethoxy-3-methyl-2-butene, commonly named ?chloracetal C5', suspected as the cause by some experts. Epidemiological investigations sought to examine the relations between occupational exposures and RCC. Methods A retrospective cohort mortality study and a nested case-control study were conducted. The cohort study included all workers who had been employed at the plant for at least 6?months between 1960 and 2003. The case-control study included an extensive search within the region for other kidney cancer cases among the cohort members. Industrial hygienists assessed occupational exposure. Results From 1968 to 2006, no significant excess mortality was observed for all causes of death or for all cancers. We found excess mortality for kidney cancer only among women. The nested case-control study showed a dose-response relation for cumulative exposure to chloracetal C5: the OR rose from 2.5 in the low-exposure category to 10.5 in the high-exposure group. Adjustment for screening attenuated this relation. Conclusions The results of the case-control study were consistent with the positive results of in vivo genotoxic tests and suggest that chloracetal C5 can have a causal role in RCC.