Aims: The present study aimed to investigate the interaction between erythrocyte phospholipid (PL) fatty acids and variants of inflammation-related genes in a Chinese population. Methods: A total of 622 patients with type 2 diabetes mellitus (T2DM) and 293 healthy subjects were included. Determination of erythrocyte PL fatty acids composition and genotyping of single nucleotide polymorphisms were conducted by standard methods. Results: A significant interaction of rs7305618 on HNFIA with C18:2n-6 and C20:4n-6 was observed: T allele carriers (TT + CT) had a higher risk of T2DM than noncarriers only when they had a higher level of C18:2n-6 or C20:4n-6, and the odds ratios (ORs) were 2.59 (95% CI 1.58-4.24; p for interaction = 0.005) and 2.49 (95% CI 1.47-4.24; p for interaction = 0.021), respectively. A significant interaction of rs8078723 at the intergenic region between PSMD3 and CSF3 with C20:5n-3 was observed: C allele carriers (CC + CT) had a lower risk of T2DM than noncarriers only when they had a higher level of C20:5n-3, and the OR was 0.44 (95% CI 0.26-0.73; p for interaction = 0.014). Conclusions: rs7305618 and rs8078723 were associated with the risk of T2DM in a Chinese population and were modulated by erythrocyte PL fatty acids composition.