Nuclear hormone receptors have been shown to be important transcription factors for regulating lipid metabolism in myeloid cells and were also implicated in differentiation processes of the myeloid lineage and macrophages. Peroxisome proliferator-activated receptor gamma (PPARgamma) seems to be a key component of lipid uptake by inducing the scavenger receptor CD36 that mediates oxidized low-density lipoprotein uptake in macrophages. Retinoic acid receptors, on the other hand, were also shown to play important roles in myeloid cell differentiation. In this study, we present evidence for a cross-talk between these two nuclear receptor pathways in myeloid cells. We show that expression level of PPARgamma increases with the degree of monocyte/macrophage commitment during maturation. Activation of PPARgamma leads to the increased expression of maturation markers (e.g., CD14, CD36). It is interesting that retinoid treatment potentiates PPARgamma's ability to induce transcription of its target genes. Retinoid-increased PPARgamma response is sufficient for enhancing lipid uptake. Our data, taken together, indicate that the expression level of PPARgamma increases during monocyte/macrophage development. PPARgamma activity can be enhanced by retinoids at least in part via increasing PPARgamma expression level. These observations can be exploited to enhance therapeutically beneficial PPAR responses in myeloid cells.