The aim of the present study was to investigate the relationship of four TNF-α SNP with inflammatory biomarkers and plasma fatty acids (FA), and the interaction among them in a population-based, cross-sectional study in São Paulo, Brazil. A total of 281 subjects, aged >19 and <60 years, participated in a cross-sectional, population-based study performed in Brazil. The following SNP spanning the TNF-α gene were genotyped: -238G/A (rs361525), -308G/A (rs1800629), -857C/T (rs1799724) and -1031T/C (rs1799964). In all, eleven plasma inflammatory biomarkers and plasma FA profile were determined. To analyse the interaction between TNF-α SNP and plasma FA, a cluster analysis was performed to stratify individuals based on eleven inflammatory biomarkers into two groups used as outcome: inflammatory (INF) and non-inflammatory clusters. The -238A allele carriers had higher TNF-α (P=0·033), IL-6 (P=0·013), IL-1β (P=0·037), IL-12 (0·048) and IL-10 (P=0·010) than the GG genotype. The -308A allele carriers also had lower levels of plasma palmitoleic acid (P=0·009), oleic acid (P=0·039), total MUFA (P=0·014), stearoyl-CoA desaturase (SCD) activity index-16 (P=0·007), SCD-18 (P=0·020) and higher levels of PUFA (P=0·046) and DHA (P=0·044). Significant interactions modifying the risk of belonging to the INF cluster were observed with inflammatory cluster as outcome between -857C/T and plasma α-linolenic acid (P=0·026), and also between -308G/A and plasma stearic acid (P=0·044) and total SFA (P=0·040). Our study contributes to knowledge on TNF-α SNP and their association with inflammatory biomarker levels, plasma FA and the interaction among them, of particular interest for the Brazilian population.