Objective To study the relation between fibrosis, pancreatic blood flow (PMBF), interstitial pH (pH(I)), and the effects of pancreaticojejunostomy (PJ) in chronic pancreatitis. Background Chronic pancreatitis is associated with low PMBF and pH(I), suggesting the existence of underlying ischemia. Methods In cats, the main pancreatic duct was partially obstructed and the animals were studied 2, 4, 6, and 8 weeks later. PJ was performed after 2 and 4 weeks of ductal obstruction and studied 4 weeks later. PMBF and pH(I) were measured before and after stimulation with secretin and cholecystokinin, pH(I) was measured with microelectrodes, PMBF by hydrogen gas clearance. Histologic analysis of the pancreas with Sirius red (collagen stain) and fast green FCF (noncollagen protein) stains allowed semiquantitative analysis of the ratio between collagen and total protein (C/TP). Results With the evolution of chronic pancreatitis, there is a progressive increase in the collagen content and C/TP ratio, a reduction in basal PMBF and pH(I), and loss of the normal response to stimulation. Early PJ restores collagen content, C/TP ratio, and basal and stimulated PMBF and pH(I) to normal. PJ performed in established CP returns the C/TP ratio to normal, improves basal PMBF, and restores the normal hyperemic response to secretion. Basal pH(I) is improved and the "acid tide" associated with secretin returns, but there is still no response to cholecystokinin. Conclusions Pancreaticojejunostomy restores the elevated collagen and C/TP ratio to normal and reverses the ischemia present in CP. The authors speculate that restoration of PMBF and its normal response to stimulation allows "regeneration" and restoration of secretory function.