Belatacept is the first T-cell costimulation blocker to be approved for the prophylaxis of organ rejection in adult kidney-transplant recipients (KTRs) and represents an alternative to calcineurin inhibitors, which are known to be nephrotoxic. After transplant, the risk of acute rejection (AR) decreases with time. Accordingly, belatacept exposures were reduced over time by changes in dose and dosing interval in the two treatment regimens tested in two phase III studies. Time-varying belatacept exposures were characterized by developing and applying a population pharmacokinetic model. Clearance and volume of central and peripheral compartments increased with baseline body weight, but there was no effect of age, gender, race, renal/hepatic function, diabetes, patient type (healthy/KTR), or dialysis on belatacept clearance. Exposure-response analyses showed that lower exposures did not compromise efficacy (as measured by AR), whereas higher exposures were associated with increased serious infections and central nervous system events.