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Acute multiple infarcts in multiple cerebral circulations (AMIMC) are thought to suggest the presence of cardioembolic sources or systemic hypercoagulopathy. However, the mechanism and the simultaneous occurrence of AMIMC are not well known. We reviewed 685 consecutive acute ischemic stroke patients who underwent diffusion-weighted imaging (DWI) within 48 hours of onset. AMIMC was defined as multiple acute DWI lesions distributed in more than one cerebral circulation (i.e., 2 anterior and 1 posterior circulations). Signal intensities on apparent diffusion coefficient (ADC) maps corresponding to acute DWI lesions were classified as 'low', 'iso-' or 'high' signals. Blood markers obtained within 24 hours after admission were compared between patients with and without AMIMC. Sixty-seven (9.8%) patients had AMIMC. Frequency of cardioembolism in AMIMC patients was only 29.9% (20/67), which was not different from non-AMIMC patients (21.7%, p = 0.16). Large-artery atherosclerosis (LAA) or small-vessel occlusion (SVO) in multiple circulations or combined LAA and SVO were identified in 34.3% (23/ 67) of AMIMC patients, although pure LAA and pure SVO were less frequent than in non-AMIMC patients. ADC signals were purely 'low' in 38 (56.7%) and 'mixed' (low with iso- or high) in 29 (43.3%). Cardioembolism tended to be associated with 'low' ADC signals (75.0%) compared with other stroke mechanisms (48.9%; p = 0.062). C-reactive protein was higher in AMIMC than in non- AMIMC patients (p = 0.009). Stroke mechanisms responsible for AMIMC are heterogeneous. ADC findings suggest that AMIMC commonly occur stepwise and may be useful in determining stroke mechanism. Systemic inflammation may be associated with the pathogenesis of AMIMC.