South Asians (SA) are at higher risk of cardiometabolic disorders than Europeans (EU), yet the potential determinants of this risk are poorly understood. We tested the hypotheses that 1) South Asians (SA) have greater muscle inflammation compared to Europeans (EU) at similar fat mass 2) differential regional adiposity in SA compared to EU is associated with enhanced muscle inflammation in SA. This cross-sectional study was conducted at a tertiary academic center in Hamilton, Ontario, Canada. The study included 29 EU and 26 SA. Quantitative real-time PCR and western blot were used to measure muscle inflammation. Statistical analysis was done using a General Linear Model. Despite having similar macrophage content to EU, SA muscle had lower levels of chemokine CCL2 compared to EU at gene expression (β -1.099, SE β 0.521, p-value 0.04) and protein (0.84 ± 0.69 versus 1.10 ± 0.60, p-value 0.052) levels. SA had more pronounced abdominal and hepatic adiposity, with smaller Intramyocellular lipid particles compared to EU (0.26 ± 0.12 μm2 versus 0.15 ± 0.06 μm2, p-value 0.02). In conclusion, CCL2 downregulation in SA may be an attempt to protect muscle against macrophage infiltration and defects in fatty acid partitioning to muscle may lead to the disproportionate adiposity and adverse cardiometabolic profile in SA.