The IL-10 family of cytokines consists of 9 members, including the immune-regulatory IL-10; Il19 is in close physical relationship with Il10 in the so-called IL-10 cytokine cluster on chromosome 1q32. While IL-10 is ubiquitously expressed, IL-19 expression is restricted to myeloid and epithelial cells. Little is known about molecular mechanisms that control tissue-specific expression of IL-10, and IL-19. Modifications in CpG-DNA methylation are a key mechanism in controlling transcription. Using bisulfite sequencing, we demonstrate that murine Il19 is methylated in CD4+ T lymphocytes. Macrophages display site-specific demethylation of Il19. The ubiquitously expressed Il10 gene is methylated to a lower degree and exhibits tissue-specific methylation patterns. DNA demethylation with 5-azacytidine resulted in an induction of IL-10, and IL-19 expression in CD4+ T cells, and CpG-DNA methylation through DNMT3a resulted in transcriptional silencing in macrophages. Thus, our findings suggest a role of CpG-DNA methylation in the regulation of Il10 and Il19.