Background: Several studies have been conducted among French nuclear workers on the effects of external exposure to ionizing radiation (IR). A pilot study on the effects of internal exposure to uranium on mortality was launched in 2005. The results of this study are presented and compared with those of other studies of nuclear workers. Methods: A cohort of 2,897 workers at the Areva-NC-Pierrelatte facility was followed from January 1, 1968, through December 31, 2006 (79,892 person-years). Mortality rates are compared to those of the French population by calculating SMRs (Standardized Mortality Ratios) and 95% confidence intervals (95% CI). External radiation exposure is reconstructed using dosimetry records. Uranium exposure is reconstructed using an occupation-exposure matrix. Six types of uranium are considered based on their isotopic composition (natural uranium and reprocessed uranium, URT) and their solubility (high-F, moderate-M, and low-S). The analysis of the association between exposures and mortality focuses on causes of death associated with IR (cancers and diseases of the circulatory system) and cancers of the target organs of inhaled uranium (lungs and lymphoid and hematopoietic tissues, LHT). Results: the cohort exhibits all-cause undermortality (SMR = 0.58; 95% CI [0.53–0.63]), all cancers (SMR = 0.72; 95% CI [0.63–0.82]), and smoking-related cancers, reflecting the healthy worker effect. A non-significant excess is observed for pleural cancers (SMR = 2.32; 95% CI [0.75–5.41]), rectal cancer, and HLL, particularly non-Hodgkin lymphoma (SMR = 1.38; 95% CI [0.63–2.61]) and chronic lymphocytic leukemia (SMR = 2.36; 95% CI [0.64–6.03]). No significant relationship with cumulative external dose was found. For low-solubility uranium, particularly URT, an increase in mortality risk of 8% to 16% per point of cumulative exposure score and 10% to 15% per year of exposure was observed. Conclusion: The Areva-NC-Pierrelatte cohort shows (non-significant) excess mortality from TLH cancers, particularly of lymphoid origin, unrelated to external exposure to IR. The pilot study suggests a link between mortality from HNS and lung cancers and exposure to poorly soluble URT. This result must be confirmed by other, larger studies, and by dose-response analyses based on the calculation of the absorbed dose of uranium at the target organ.