Systemic lupus erythematosus (SLE) is a polygenic disorder affecting 1:1000 adults. Recent data have implicated interferons in the pathogenesis. We examined H4 acetylation and gene expression in monocytes from patients with SLE to define alterations to the epigenome. Monocytes from 14 controls and 24 patients were used for analysis by chromatin immunoprecipitation for H4 acetylation and gene expression arrays. H4 acetylation is significantly altered in monocytes from patients with SLE. Although there was a relationship between increased H4 acetylation and gene expression the two gene sets were not concordant. The most significant relationship for both genes with increased H4 acetylation and increased gene expression was the potential for transcriptional regulation by IRF1. Alpha-interferon was a significant contributor to gene expression patterns in SLE, but the greatest concordance was seen in the enrichment of certain transcription factor binding sites upstream of genes with increased H4 acetylation in SLE and genes with increased H4 acetylation after alpha-interferon treatment. We conclude that SLE is associated with a globally altered epigenome. Multiple lines of evidence implicate the interferon pathway. Altered epigenetic patterns could contribute to the perpetuation of disease by molding the gene set competent for expression.