This study evaluated the response of global histone H4 acetylation (H4ac), histone deacetylase 2 (HDAC2) activity, as well as the production of proinflammatory cytokines and monocyte phenotypes of lean and obese males after exercise. Ten lean and ten obese sedentary men were submitted to one session of strenuous exercise, and peripheral blood mononuclear cells (PBMC) were stimulated in vitro with lipopolysaccharide (LPS). Global H4ac levels, HDAC2 activity in PBMC, and IL-6, IL-8, and TNF-α production were analyzed. Monocyte phenotype was determined in accordance with the expression of CD14 and CD16. At rest, obese individuals presented higher frequency of proinflammatory CD14+CD16+ monocytes. LPS induced a significant augment in global H4ac and in the production of IL-6, IL-8, and TNF-α mainly in obese individuals. After exercise, the increased production of IL-8 and TNF-α and peripheral frequency of CD14+CD16+ were observed in both groups. In addition, exercise also induced a significant hyperacetylation of histone H4 and decreased HDAC2 activity in both nonstimulated and LPS-stimulated PBMC of obese individuals. Our data indicate that the obesity impacts on H4ac levels and that strenuous exercise leads to an enhanced chronic low-grade inflammation profile in obesity via an imbalance on H4ac/HDAC2.