Genes increased in males involve regulation of cholesterol metabolism and steroidogenesis. In this study we verified that a number of genes that are important in regulating cholesterol influx into cells and steroidogenesis are more highly expressed in the spleen of males prior to, or during, the innate immune response to coxsackievirus B3 (CVB3) infection. Genes with a higher expression in males are shown in pink boxes, genes with lower expression in males in green boxes and genes we did not examine in purple boxes. We suggest the following hypothesis as one possible scenario leading to increased inflammation in males. Haptoglobin (Hp) is known to bind Apo-A1 preventing the conversion of proinflammatory low-density lipoproteins (LDLs) to anti-inflammatory high-density lipoproteins (HDLs), thereby increasing the LDL levels. Elevated phospholipase A2 (PLA2) in males may facilitate the oxidation (Ox) of LDL allowing it to bind the macrophage scavenger receptor (Msr1/MSR) and import LDL-cholesterol into immune cells, particularly macrophages. Increased levels of squalene synthase in males may facilitate intracellular cholesterol synthesis in immune cells. PLA2 is an endogenous ligand for translocator protein 18 kDa (TSPO), the rate-limiting step for steroidogenesis within cells. Cyp2e1 participates in the metabolism of cholesterol and steroids and contributes to an increased proinflammatory response in males. Increased production of androgens within macrophages allows the androgen receptor (AR) to release from its chaperone Hsp90 and move to the nucleus to stimulate the proinflammatory immune response associated with increased myocarditis and heart failure in males following CVB3 infection.