Diets varying in saturated (SFA) and monounsaturated fatty acid (MUFA) content can impact glycemic control; however, whether underlying differences in genetic make-up can influence blood glucose responses to these dietary fatty acids is unknown. We examined the impact of dietary oils varying in SFA/MUFA content on changes in blood glucose levels (primary outcome) and whether these changes were modified by variants in the stearoyl-CoA desaturase (SCD) gene (secondary outcome). Obese men and women participating in the randomized, crossover, isocaloric, controlled-feeding Canola Oil Multicenter Intervention Trial II consumed 3 dietary oils for 6 wk, with washout periods of ˜6 wk between each treatment. Diets studied included a high SFA/low MUFA Control oil (36.6% SFA/28.2% MUFA), a conventional canola oil (6.2% SFA/63.1% MUFA), and a high oleic acid canola oil (5.8% SFA/74.7% MUFA). No differences in fasting blood glucose were observed following the consumption of the dietary oils. However, when stratified by SCD genotypes, significant SNP-by-treatment interactions on blood glucose response were found with additive models for rs1502593 (p=0.01), rs3071 (p=0.02), and rs522951 (p=0.03). The interaction for rs3071 remained significant (p=0.005) when analyzed with a recessive model, where individuals carrying the CC genotype showed an increase (0.14±0.09 mmol/L) in blood glucose levels with the Control oil diet, but reductions in blood glucose with both MUFA oil diets. Individuals carrying the AA and AC genotypes experienced reductions in blood glucose in response to all 3 oils. These findings identify a potential new target for personalized nutrition approaches aimed at improving glycemic control.