For the performance assessment of radioactive waste disposal, it is critical to predict the mobility of radionuclides in the geological barrier that hosts it. A key challenge consists of assessing the transferability of current knowledge on the retention properties deduced from model systems to in natura situations. The case of the redox-sensitive element uranium in the Callovo-Oxfordian clay formation (COx) is presented herein. Extensive experimental work was carried out with respect to parameters affecting uranium speciation (pH, PCO2, [Ca] and redox potential) with illite, COx clay fraction and raw COx claystone. The “bottom-up” approach implemented, with illite and montmorillonite as reactive phases, quantitatively explains the adsorption results of U(VI) and U(IV) on COx. While retention is high for U(IV) (Rd∼104 L kg−1), it remains very low for U(VI) (Rd∼4 L kg−1) due to the formation of soluble ternary Ca(Mg)–U(VI)-carbonate complexes. The applicability of the sorption model was then assessed by comparing predictive analyses with data characterizing the behavior of naturally-occurring U (<3 mg kg−1). The COx clay phase is the largest reservoir of naturally-occurring U (∼65%) but only a small fraction appears to be adsorbed (∼1%). Under representative site conditions (especially with respect to reducing conditions), we have concluded that ternary U(VI) complexes control U speciation in solution while U(IV) surface species dominate U adsorption, with Rd values > 70 L kg−1. (Elsevier)