Scope: Reduced amylase 1 (AMY1) copy numbers are associated with obesity, insulin resistance, and inflammation. Although mechanisms linking AMY1 copy number with metabolic disorders are poorly understood, recent findings suggest that lipids play a key role. Methods and results: Plasma lipidomic signatures associated with AMY1 copy number are explored in 57 non-diabetic overweight/obese subjects aged 18–60. Serum amylase and inflammatory cytokines levels are also measured. AMY1 copy number is strongly associated with the serum amylase concentration. Participants are divided into low-(≤4) and high-(>4) AMY1 carriers based on the median. Low-AMY1 carriers have higher BMI and fat mass. They also have higher levels of dihexosylceramides (R = −0.27, p = 0.044), cholesterol esters (CE) (R = −0.32, p = 0.020), alkylphosphatidylcholines [PC(O)] (R = −0.33, p = 0.014), and sphingomyelins (SM) (R = −0.38, p = 0.005). From 459 lipid species, 28 differ between low- and high-AMY1 carriers. These include CE species with long-chain PUFA; PC(O) and PC plasmalogens containing arachidonic acid; and PC, mono-, di-, and tri-hexosylceramides, and SM containing saturated fatty acids (mainly C16:0 and C20:0). This lipidomic signature is strongly associated with inflammatory cytokines, which are also negatively associated with the AMY1 copy number. Conclusion: A lipidomics signature associated with low AMY1 copy numbers is revealed, which is linked to obesity and chronic low-grade inflammation.