BACKGROUND AND PURPOSE: Gadolinium-enhanced MR imaging is currently the reference standard for detecting active inflammatory lesions in patients with multiple sclerosis. The sensitivity of MR imaging for this purpose may vary according to the physicochemical characteristics of the contrast agent used and the acquisition strategy. The purpose of this study was to compare detection of gadoliniumenhancing lesions or active disease following a single or cumulative dose of a macrocyclic gadolinium-based contrast agent with different image acquisition delays in patients with clinically isolated syndrome or relapsing multiple sclerosis. MATERIALS AND METHODS: All patients received a first dose (0.1 mmol/kg) of gadobutrol and, 20 minutes later, a second dose (0.1 mmol/kg), with a cumulative dose of 0.2 mmol/kg. Two contrast-enhanced T1-weighted sequences were performed at 5 and 15 minutes after the first contrast administration, and 2 additional T1-weighted sequences at 5 and 15 minutes after the second contrast administration with a 3T magnet. RESULTS: One hundred fifteen patients were considered evaluable. A significantly larger number of lesions were detected in scans obtained at 5 and 15 minutes after the second contrast injection compared with scans obtained at 5 and 15 minutes after the first injection (P<.001). The number of patients with active lesions on MR imaging was significantly higher after the second dose administration (52.0%, first dose versus 59.2%, second dose; P < .001). CONCLUSIONS: Cumulative dosing of a macrocyclic gadolinium-based contrast agent increases detection of enhancing lesions and patients with active lesions. These data could be considered in the design of MR imaging protocols aimed at detecting active multiple sclerosis lesions.