This study investigated the associations between the c.189G > T polymorphism of the insulin receptor substrate-1 (IRS-1) gene and the growth and litter size-related traits in the Native rabbit in Middle Egypt (NMER). One hundred sixty-two NMER rabbits were genotyped by RFLP-PCR using Sau3AI restriction enzyme and the associations of the reported genotypes with body weights at 5th, 6th, 8th, 10th, and 12th week old, body gain, and daily gain plus, the litter size-related traits were determined. Additionally, the genotypic and allelic frequencies, the effective (Ne) and observed (NA) numbers of alleles, observed (Ho) and expected (He) heterozygosity, Hardy-Weinberg equilibrium (HWE), and the decrease in heterozygosity because of inbreeding (FIS) were calculated. Three genotypes; GG, GT, and TT with 0.65, 0.33, and 0.02 frequencies, respectively which fit HWE were reported. These genotypes displayed a marked low FIS value. Significant associations of the genotypes with the body weights, and gains, except at the 5th week old determined with superiority of the GT genotype compared with the other genotypes. All reported litter size-related traits significantly varied among different genotypes. In summary, the c.189G > T SNP of the IRS-1 gene is an effective genetic marker to improve growth performance and litter size traits of the NMER rabbits.