Glucocorticoids (GCs) bind to the glucocorticoid receptor (GR) and are effective anti-inflammatories, a.o. against rheumatoid arthritis (RA), but may also cause many (metabolic) side effects. Interestingly, peroxisome-proliferator activated nuclear receptor (PPAR) agonists counteract symptoms similar to GC side effects and also suppress inflammation. This study explores how PPAR agonists influence the immunosuppressive and metabolic effects of GCs. DEX reduced the inflammatory TNFα response in mouse L929sA fibroblasts with a stably integrated E-selectin or IL-8-based luciferase reporter. This was further enhanced by PPARα agonist GW7647 and PPARγ agonist rosiglitazone, but not by other PPARα or PPARβ/δ agonists. After TNF stimulation, the suppression of proinflammatory gene transcription was stronger after combined DEX and GW7647 treatment than after single ligand treatments. As a model mimicking RA more closely, fibroblast-like synoviocytes (FLS) were isolated from four female osteoarthritis patients and cultured ex vivo. FLS from all patients expressed GR, PPARα and PPARγ proteins, with DEX downregulating GR levels. Expression of metabolic genes Pdk4 and Angptl4 was increased by DEX and GW7647 alone and to a higher extent by their combination. However, the cooperative reduction of pro-inflammatory genes by DEX and GW7647 was not observed in TNF-stimulated FLS. In collagen-induced arthritis mice, dexamethasone increased white adipose tissue weight, which was partially counteracted by GW7647. However, GW7647 did not affect the DEX-mediated suppression of arthritis severity and immune cell counts. In conclusion, PPAR agonists can influence the metabolic effects of GCs, but the immunosuppressive effects only in a cell-type specific manner.