Heme oxygenase-1 (HO-1) is an anti-inflammatory enzyme that maintains homeostasis during cellular stress. Given previous findings that shorter length variants of a HO-1 promoter region GT n microsatellite polymorphism are associated with increased HO-1 expression in cell lines, we hypothesized that shorter variants would also be associated with increased levels of HO-1 expression, less inflammation and lower levels of inflammation-associated viral replication in human immunodeficiency virus (HIV)-infected subjects. Healthy donors (n= 20) with shorter GT n repeats had higher HO-1 mRNA transcript in peripheral blood mononuclear cells stimulated with lipopolysaccharide (r=− 0.38, P= 0.05). The presence of fewer GT n repeats in subjects with untreated HIV disease was associated with higher HO-1 mRNA levels in peripheral blood (r=− 0.41, P= 0.02); similar observations were made in CD14+ monocytes from antiretroviral-treated subjects (r=− 0.36, P= 0.04). In African-Americans, but not Caucasians, greater GT n repeats were correlated with higher soluble CD14 levels during highly active antiretroviral therapy (r= 0.38, P= 0.007) as well as higher mean viral load off-therapy (r= 0.24, P= 0.04). These data demonstrate that the HO-1 GT n microsatellite polymorphism is associated with higher levels of HO-1 expression and that this pathway may have important effects on the association between inflammation and HIV replication.