The acquired capability of evading apoptosis is one of the prerequisites for cancer development, and NF-kappaB plays a critical role by inducing anti-apoptotic molecules. In this study, we firstly carried out an expression-cloning approach to isolate the responsible molecules in the NF-kappaB activation pathway with the defective mutant cell line, COS-A717. This cell line shows reduced constitutive basal activity of NF-kappaB as compared with the parental COS cells. We successfully isolated genes with compensating activity for the pathway, and one gene encoded B-cell activating factor receptor (BAFF-R). However, a Northern blot analysis revealed that the BAFF-R expression is not only limited to cells of B cell origin, but also is found in those with nonhematopoietic origins. In the human fibrosarcoma cell line HT1080, an immunohistochemical analysis revealed that the expression of BAFF-R is not on the cell surface, but in the cytoplasm. The expression of BAFF was also detected, and the reduction of endogenous BAFF or BAFF-R by siRNA decreased the basal NF-kappaB activity. Lastly, from clinicopathological specimens, the associated expression of BAFF-R and BAFF was demonstrated in osteosarcoma. We propose that an aberrant BAFF/BAFF-R-dependent autocrine mechanism may play a role in the development of certain types of cancer cells.