Background: Restoration of the body's ability to produce insulin by regeneration of ß-cells is an essential step toward the management of diabetes. REG Ia is released from damaged ß-cell and facilitates their renewal. However, genetic variants of REG Ia and their clinical associations are overlooked areas. This study was designed to identify polymorphisms of REG Ia gene exon 1 and its association with type 2 diabetes. Methods: This was a case-control study conducted on individuals n=51 both diabetics (n=36) (aged, 52±9 years; males 25, females 11) (group II) and age-related controls (n=15) (aged, 50±3 years; males 9, female 6) (group I) recruited from PNS Shifa Hospital, Karachi. The samples were amplified, and the gene was sequenced to identify polymorphisms. Chi-square (?2) test was used to determine whether each polymorphism obeys Hardy-Weinberg equilibrium (HWE). Odds ratios, 95% confidence interval along with corresponding p values were calculated through logistic regression analysis. p < 0.05 was considered statistically significant. Results: A set of two single nucleotide polymorphisms (SNPs) were detected in the REG Ia gene exon1 in the subjects under study. SNPs studied were: g.-243T>G [rs 283890], and g.-385T>C [rs10165462]). Both variants g-243T>G, and g-385T>C showed significant association (?2=12.8, p=0.0003, ?2=13.8, p=0.0002) with smoking. The allele G showed an eight-fold increased risk of disease in smokers while allele C had less chance of the disease in smokers as compared to non-smokers. Conclusion: Among the SNPs detected in exon 1 of the gene for REG Ia, the g. -385T>C and g. -243T>G variants showed an association with smoking in type 2 diabetes and the SNP -243G (rs 283890) was found to increase the risk of disease in smokers.