The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of a large group of nuclear receptors controlling the proliferation of peroxisomes that is involved in the downregulation of macrophage functions. Here, we report that PPAR-γ was constitutively expressed in rat primary microglial cultures and that such expression was downregulated during microglial activation by endotoxin (LPS). The presence of the PPAR-γ natural ligand 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) counteracted the repression of PPAR-γ expression caused by LPS. In microglial cultures stimulated by LPS, interferon-γ (IFN-γ) or by their combination, 15d-PGJ2 reduced the production of nitric oxide (NO) and the expression of inducible NO synthase (iNOS). The inhibitory effect was dose-dependent and did not involve an elevation of cyclic AMP, a second messenger known to inhibit NOS expression in microglia. In addition, 15d-PGJ2 down-regulated other microglial functions, such as tumour necrosis factor-α (TNF-α) synthesis and major histocompatibility complex class II (MHC class II) expression. The effects of 15d-PGJ2 occurred, at least in part, through the repression of two important transcription factors, the signal transducer and activator of transcription 1 and the nuclear factor κB, known to mediate IFN-γ and LPS cell signalling. Our observations suggest that 15d-PGJ2, the synthesis of which is likely to occur within the brain, could play an important role in preventing brain damage associated with excessive microglial activation.