Background: We have recently observed that the joint genotype Acid Phosphatase locus 1-Adenosine deaminase locus 1 (ACP 1-ADA 1) cooperate with Phospho Tyrosine Phosphatase, non-receptor type 22 (PTPN22) in the susceptibility to Type 1 Diabetes (T1D). Since T1D has been found associated with sex, maternal age at birth, Adenosine Deaminase locus 2 (ADA 2) genotype and p53 codon 72 genotype we have investigated the possible effects of these variables on the association of T1D with PTPN22 and with ACP 1-ADA 1 joint genotype. Methods: We have reexamined the data on 314 children with T1D and on 770 controls from the White population of Rome. PTPN22, ADA 2 and p53 codon 72 genotypes were determined by DNA analysis. Statistical analysis were carried out by commercial software (SPSS). Results: The genetic and non genetic variables considered, in particular ADA 2 *2 carrier, p53 codon 72 *Pro carrier, male sex and maternal age greater than 32 years, have a positive effect on the strength of association between PTPN22 and T1D but tend to have a negative effect on the strength of association between ACP 1-ADA 1 joint genotype and T1D. Conclusions: The results suggest that although PTPN22 and ACP 1-ADA 1 genetic complex cooperate in the susceptibility to T1D, the mechanisms underlying the association of the two genetic systems with the disease are different.