In this article, we confirm the positive association of acid phosphatase locus 1 (ACP1)*A/adenosine deaminase locus 1 (ADA1)*2 gametic type with type 1 diabetes (T1D) previously reported and show a negative correlation between the frequency of this gametic type with past malarial morbidity in Sardinia. One hundred seven adult women with T1D and 385 healthy adult women from the Caucasian population of Central Italy have been studied. Data on 1384 children from the central area of Sardinia have also been reexamined. T1D subjects show a highly significant increase of ACP1*A/ADA1*2 gametic type compared with healthy subjects from the same population (P = 0.003). The frequency of ACP1*A/ADA1*2 gametic type is decreasing with increasing past malarial morbidity. Because ADA1*2 allele decreases the activity of *A allele and since low ACP1 activity decreases Zeta-chain-associated protein kinase with molecular weight 70 kDa (Zap70) activity resulting in weak T-cell receptor signalling an epistatic interaction involving ADA1, ACP1 and Zap70 seems a likely mechanism for the associations observed.