Autoimmune pancreatitis (AIP) is a rare cause of chronic pancreatitis and mimics pancreatic cancer. Although there is strong interest in research, etiology and pathophysiology of AIP are still unknown. Therefore, we analyzed a total of 92 MRL/Mp-mice of either sex, which are prone to develop AIP, in four different age-groups (8-12, 16-20, 24-28, 32-40 weeks). Using intravital fluorescence microscopy, histology, laboratory analysis and Western blot, onset, severity and pathophysiological mechanisms of AIP were evaluated. Female animals showed in vivo an age-dependent increase of intra-pancreatic leukocyte accumulation as well as a loss in functional capillary perfusion. In contrast, intra-pancreatic inflammation in male mice was less pronounced and not age-dependent. Furthermore, pancreatic tissue specimen of female animals exhibited major organ destruction with significantly higher values of mean pathological scores (1.5±0.3 vs. 0.2; p<0.05) as well as significantly increased CD4-, CD8-, CD11b- and CD138-positive cells compared to male animals of the same age. Interestingly, there was a significant positive correlation between intravascular leukocyte adherence and the histopathological score of the pancreas, indicating a determining role of the innate immune system for the late onset of AIP. The present study shows that the onset of AIP is characterized by an inflammatory response and microcirculatory failure, most probably constituting initiators and propagators of this autoimmune disease.