The acquired capability of evading apoptosis is one of the prerequisites for cancer development, and NF‐κB 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‐κB activation pathway with the defective mutant cell line, COS‐A717. This cell line shows reduced constitutive basal activity of NF‐κB 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‐κB 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.