Peroxisome proliferator-activated receptor gamma (PPARgamma) gained considerable interest as a therapeutic target during chronic inflammatory diseases. Remarkably, the pathogenesis of diseases such as multiple sclerosis or Alzheimer is associated with impaired PPARgamma expression. Considering that regulation of PPARgamma expression during inflammation is largely unknown, we were interested in elucidating underlying mechanisms. To this end, we initiated an inflammatory response by exposing primary human macrophages to lipopolysaccharide (LPS) and observed a rapid decline of PPARgamma1 expression. Because promoter activities were not affected by LPS, we focused on mRNA stability and noticed a decreased mRNA half-life. As RNA stability is often regulated via 3'-untranslated regions (UTRs), we analyzed the impact of the PPARgamma-3'-UTR by reporter assays using specific constructs. LPS significantly reduced luciferase activity of the pGL3-PPARgamma-3'-UTR, suggesting that PPARgamma1 mRNA is destabilized. Deletion or mutation of a potential microRNA-27a/b (miR-27a/b) binding site within the 3'-UTR restored luciferase activity. Moreover, inhibition of miR-27b, which was induced upon LPS exposure, partially reversed PPARgamma1 mRNA decay, whereas miR-27b overexpression decreased PPARgamma1 mRNA content. In addition, LPS further reduced this decay. The functional relevance of miR-27b-dependent PPARgamma1 decrease was proven by inhibition or overexpression of miR-27b, which affected LPS-induced expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-6. We provide evidence that LPS-induced miR-27b contributes to destabilization of PPARgamma1 mRNA. Understanding molecular mechanisms decreasing PPARgamma might help to better appreciate inflammatory diseases.