Animal models have indicated that alpha-tocopherol may protect against type 1 diabetes mellitus (DM1). Epidemiological data on the subject are scarce. The objective of this study was to evaluate the association of serum alpha-tocopherol concentration and risk of DM1 in a cohort of initially non-diabetic siblings of children affected by DM1 (n = 722). We used two study designs: 1) Siblings who progressed to DM1 were compared with control siblings who remained negative for DM1-associated autoantibodies in a nested case-control study design. 2) All siblings with DM1-associated autoantibodies were prospectively followed for DM1. In both designs, high concentrations of serum alpha-tocopherol tended to be associated with a lower risk of DM1 (p = 0.08 and 0.09, respectively). Although the results did not reach statistical significance, they support the hypothesis that high alpha-tocopherol levels may protect against DM1.