Multiple myeloma (MM) remains largely incurable despite conventional and high-dose therapies. Therefore, novel biologically based treatment approaches are urgently required. Here we demonstrate that expression of peroxisome proliferator-activated receptor γ (PPARγ) in MM cells and its agonists 15-d-PGJ2 and troglitazone completely abolished IL-6-inducible MM cell proliferation and induced apoptosis through affecting expression of multiple cell cycle or apoptosis genes, whereas PPARγ antagonist GW9662 and PPARα agonist WY14643 did not display this inhibitory effect. These PPARγ agonists significantly inhibited DNA binding and transactivation of STAT3 bound to the promoter of target genes in chromatin, but did not affect the expression of IL-6 receptor and phosphorylation of JAK/STAT3, MAPK, and PI3K/Akt. Interestingly, although inactivation of STAT3 by PPARγ agonists is in a PPARγ-dependent manner, the molecular mechanism by which two structurally distinct PPARγ agonists suppress IL-6-activated STAT3 shows the divergent interactions between PPARγ and STAT3 including direct or SMRT-mediated association.