Chronic imaging of cerebral blood flow (CBF) is an important tool for investigating vascular remodeling after injury such as stroke. Although techniques such as Laser Speckle Contrast Imaging (LSCI) have emerged as valuable tools for imaging CBF in acute experiments, their utility for chronic measurements or cross-animal comparisons has been limited. Recently, an extension to LSCI called Multi-Exposure Speckle Imaging (MESI) was introduced that increases the quantitative accuracy of CBF images. In this paper, we show that estimates of chronic blood flow are better with MESI than with traditional LSCI. We evaluate the accuracy of the MESI flow estimates using red blood cell (RBC) photographic tracking as an absolute flow calibration in mice over several days. The flow measures computed using the MESI and LSCI techniques were found to be on average 10% and 24% deviant (n=9 mice), respectively, compared with RBC velocity changes. We also map CBF dynamics after photo-thrombosis of selected cortical microvasculature. Correlations of flow dynamics with RBC tracking were closer with MESI (r=0.88) than with LSCI (r=0.65) up to 2 weeks from baseline. With the increased quantitative accuracy, MESI can provide a platform for studying the efficacy of stroke therapies aimed at flow restoration.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 April 2013; doi:10.1038/jcbfm.2013.57.