The Osteopontin (OPN) encoding gene, SPP1, can be considered as a candidate for genetic susceptibility to type 1 diabetes (T1D) because of its known function in immune response and inflammation. This work aimed to evaluate the role of SPP1 gene in susceptibility to T1D. Patients (238: 130 male, 108 female) and unaffected adult control individuals (137: 68 males and 69 females) have been genotyped for three variants in the SPP1 gene: -156 (G/GG) and -66 (T/G) in the promoter and a biallelic ins/del variant (TG/TGTG) at +245 in the first intron. The G allele at the -66 SNP had significantly higher frequency in controls than T1D patients. Interestingly, case-control comparison in males showed no significant association, whereas the association was confirmed in females. These results suggest that SPP1 can play a role as susceptibility gene, possibly by a sex-specific mechanism acting in the autoimmune process.