Annexing are a family of calcium-dependent phospholipid binding proteins; to date thirteen members of the family have been identified. Very little is known about annexin III (ANX III). Our recent findings (Sekar et al., 271:8295, 1996) indicated, contrary to a previous report, that ANX III is not involved in the hydrolysis of cyclic inositol phosphate. In this study, we report our findings on immunohistochemical distribution in paraffin sections of ANX III in pancreas, liver, kidney, spleen, prostate and mammary gland of rat, guinea pig and human. These results indicate that high expression of ANX III is present in the cells of the ductal system of many organs. Very prominent ductal localization was observed in the ducts of the pancreas, liver, prostate and breast. Both cytoplasmic and perinuclear staining of the cells or large ducts and ductules was observed. Normal pancreatic islets were devoid of staining. In guinea pig kidney, ANX III was observed in collecting tubules, but not in proximal or distal convoluted tubules. For rat kidney, a similar distribution has been observed with annexin IV, while ANX III was essentially absent. This may indicate species variability in the expression of ANX isoforms. Conclusion: Although the functional significance of ANX III is still unclear, the very prominent distribution in ductal cells may indicate its role in secretion.