Cyclooxygenase-2 (COX-2) is an important enzyme in inflammation. In this study, we investigated the underlying molecular mechanism of the synergistic effect of rottlerin on interleukin$1{eta}$ (IL-$1{eta}$)-induced COX-2 expression in MDA-MB-231 human breast cancer cell line. Treatment with rottlerin enhanced IL-$1{eta}$-induced COX-2 expression at both the protein and mRNA levels. Combined treatment with rottlerin and IL-$1{eta}$ significantly induced COX-2 expression, at least in part, through the enhancement of COX-2 mRNA stability. In addition, rottlerin and IL-$1{eta}$ treatment drove sustained activation of p38 Mitogen-activated protein kinase (MAPK), which is involved in induced COX-2 expression. Also, a pharmacological inhibitor of p38 MAPK (SB 203580) and transient transfection with inactive p38 MAPK inhibited rottlerin and IL-$1{eta}$-induced COX-2 upregulation. However, suppression of protein kinase C ${delta}$ (PKC ${delta}$) expression by siRNA or over-expression of dominant-negative PKC ${delta}$(DN-PKC-${delta}$) did not abrogate the rottlerin plus IL-$1{eta}$-induced COX-2 expression. Furthermore, rottlerin also enhanced tumor necrosis factor-${alpha}$ (TNF-${alpha}$), phorbol myristate acetate (PMA), and lipopolysaccharide (LPS)-induced COX-2 expression. Taken together, our results suggest that rottlerin causes IL-$1{eta}$-induced COX-2 upregulation through sustained p38 MAPK activation in MDA-MB-231 human breast cancer cells.