Sun exposure is associated with lower death rates for pancreatic cancer in some ecological studies. Skin exposure to UVB light induces cutaneous production of precursors to 25-hydroxyvitamin D [25(OH)D]. Pancreatic islet and duct cells express 25(OH)D(3)-1alpha-hydroxylase that generates the biologically active 1,25(OH)(2) vitamin D form. Thus, 25(OH)D concentrations could affect pancreatic function and possibly pancreatic cancer etiology. We conducted a prospective nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention cohort of male Finnish smokers, ages 50 to 69 years at baseline, to test whether more adequate vitamin D status, as determined by prediagnostic serum 25(OH)D concentrations, was associated with lower pancreatic cancer risk. Two hundred incident exocrine pancreatic cancer cases that occurred between 1985 and 2001 (up to 16.7 years of follow-up) were matched by age and date of blood draw to 400 controls who were alive and free of cancer at the time the case was diagnosed. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. Higher vitamin D concentrations were associated with a 3-fold increased risk for pancreatic cancer (highest versus lowest quintile, >65.5 versus <32.0 nmol/L: OR, 2.92; 95% CI, 1.56-5.48, P(trend) = 0.001) that remained after excluding cases diagnosed early during follow-up. Contrary to expectations, subjects with higher prediagnostic vitamin D status had an increased pancreatic cancer risk compared with those with lower status. Our findings need to be replicated in other populations and caution is warranted in their interpretation and implication. Our results are intriguing and may provide clues that further the understanding of the etiology of this highly fatal cancer.