In systemic lupus erythematosus, TNFalpha is elevated in the serum and correlates with disease activity and triglyceride levels. The stimuli that drive TNFalpha in this setting are incompletely understood. This study was designed to evaluate monocyte chromatin at the TNFalpha locus to identify semi-permanent changes that might play a role in altered expression of TNFalpha. SLE patients with relatively quiescent disease (mean Physician Global Assessment=0.6) and healthy controls were recruited for this study. TNFalpha expression was measured by intracellular cytokine staining of different monocyte subsets in patients (n=24) and controls (n=12). Histone acetylation at the TNFalpha locus was measured by chromatin immunoprecipitation using a normalized quantitative PCR in patients (n=46) and controls (n=24). There were no differences in the overall fractions of cells expressing CD14 in SLE patients compared to controls; however, the fraction of DR+/CD16+ cells expressing CD14 was slightly higher as was true in the monocyte subset defined by DR+/CD11b+. Within the monocyte population defined by physical characteristics and DR+/CD14+, TNFalpha expressing cells were more frequent in SLE patients compared to controls. Both the fraction of positive cells and the mean fluorescence intensity were higher in patients than controls. Consistent with this was the finding that monocytes from patients had increased TNFalpha transcripts and more highly acetylated histones at the TNFalpha locus compared to controls. Furthermore, patients with the highest levels of TNFalpha histone acetylation were more likely to have had consistently elevated erythrocyte sedimentation rates, and to have required cytotoxic use. Histone acetylation, associated with increased transcriptional competence of TNFalpha, may play a role in certain inflammatory aspects of the disease.