To investigate the pathogenesis of pain in chronic pancreatitis, tissue resected from 50 patients with this condition was examined by light microscopy. An examiner, blinded to clinical and pathological data, graded perineural fibrosis, inflammation and the composition of inflammatory infiltrate in 2132 separate perineural fields. Correlation of perineural fibrosis and inflammation grading with alcohol ingestion and pain severity was insignificant. Pain severity did correlate with the timing of alcohol consumption. Although calcification significantly affected pain severity, the status of duct dilatation was not significant. Eosinophils were observed in disproportionate numbers in the perineural infiltrate. The correlation of percentage eosinophilic infiltrate and pain severity was highly significant. Timing of alcohol consumption also correlated significantly with the percentage eosinophilic infiltration. As eosinophils are known to be cytotoxic and injurious to tissue by liberation of enzymes through degranulation, the findings of this study suggest that the pain of chronic pancreatitis may be mediated by perineural eosinophils, through a chemotactic mechanism involving alcohol.