Herpes virus entry mediator (HVEM) is a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF14), which serves as a receptor for herpes viruses and cytokines such as lymphotoxin-alpha (LT-alpha) and LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells). We aimed to explore the associations of HVEM with human obesity. HVEM gene expression and protein levels were studied in total adipose tissue and in their fractions (isolated adipocytes and stromovascular cells (SVCs)) obtained from 81 subjects during elective surgical procedures. HVEM -241GA and -14AG gene polymorphisms were also studied and associated with obesity measures in 840 subjects. Visceral adipose tissue had significantly higher expression of HVEM than subcutaneous adipose tissue (P < 0.0001). Obese patients had significantly higher subcutaneous HVEM gene expression (P = 0.03) and protein levels (P = 0.01) than lean subjects. HVEM gene expression and protein levels were found in both isolated adipocytes and SVCs. These findings were confirmed in primary cultures from human preadipocytes, in which a significant increase in HVEM was observed during the differentiation process. HVEM -241GA and -14AG gene polymorphisms were associated with obesity, diastolic pressure, several inflammatory parameters (C-reactive protein and interleukin 18 (IL-18)), and circulating LIGHT concentrations. A sample of men with the G241A gene polymorphism also showed an increased serum titer of IgG antiherpes virus 1. These results provide evidences of an existing relationship between HVEM and obesity, which suggest that this TNF superfamily receptor could be involved in the pathogenesis of obesity and inflammation-related activity.