The expression levels of cyclooxygenase (COX)-2 and the prostaglandin E2 (PGE2) content have been associated with poor prognosis in patients with colorectal cancer (CRC). There is a strong correlation between COX-2 expression and PGE2 production in tissues from CRC patients, suggesting an important role for COX-2 on the regulation of PGE2 production. Previous studies by the present authors, where CRC patients were divided into high- or low-COX-2 expressing tumors, displayed important differences in the expression levels of several transcription factors involved in carcinogenesis. Among them, FBJ murine osteosarcoma viral oncogene homolog B (FosB), which is a member of the activator protein-1 complex, was the highest upregulated transcription factor in patients with high expression levels of COX-2. The present study aimed to investigate the role of FosB on the COX-2/PGE2 axis in CRC cells with high COX-2 expression levels. Interference RNA technology was used to knockdown FosB expression in HCA-7 cells, and 72 h later the messenger (m)RNA expression levels of COX-1 and COX-2, as well as the PGE2 content, were measured. The results indicated that FosB knockdown decreased the expression levels of COX-2 but did not affect the PGE2 content or the mRNA expression levels of COX-1. The present findings suggest an important role for FosB on the regulation of COX-2 expression, but no effect on the regulation of the PGE2 levels. In addition, the present results imply independent regulatory mechanisms for COX-2 expression and PGE2 content.