Chronic exposure to metals or toxic elements may contribute to many diseases. Lead (Pb), cadmium (Cd), and arsenic (As) were toxic agents in the environment. Selenium (Se), cobalt (Co), copper (Cu), and zinc (Zn) are essential trace elements for human, but they may do harm to health beyond normal concentrations. The interactions among multiple elements are complicated and remain unclear. Toxic elements may cause a threat through inflammation. Tumour necrosis factor-α (TNF-α) is an important mediator of inflammation, and several single nucleotide polymorphisms (SNPs) have been identified in the human TNF gene promoter. Our aim is to analyse how TNF-α gene polymorphisms and multi-elements interaction influence serum TNF-α level. A total of 462 metal industrial workers who have received health examination in Kaohsiung Medical University Hospital were recruited. The blood samples were sent for biochemical analyses, TNF-α genotype analyses (−238G>A, −308G>A, −857C>T, −863C>A, −1031T>C), and measurement of blood multi-elements concentrations (Pb, Cd, As, Se, Co, Cu, Zn) and serum TNF-α level. Mixed-effect models were used for analysing complex interactions of multi-elements and multiple TNF-α SNPs. All elements have positive correlation with serum TNF-α level, and the effects may be modified by TNF-α gene polymorphisms. Interactions between TNF-α gene polymorphisms and multi-elements may influence serum TNF-α level. We suggest that the workers with susceptible TNF-α genotypes which may induce higher serum TNF-α level should pay more attention to metal toxicity.