Follicular lymphoma (FL) cells are malignant counterparts of germinal centre (GC) B cells. Microenvironment of FL B cells has an important role in the progression of FL and might also have an impact on the treatment of FL. CD40 is an important mediator of microenvironmental survival signals in GCs. Here we studied responses of CD40 signalling on TRAIL-, dexamethasone- and doxorubicin-induced apoptosis in three human FL cell lines. In two of the FL cell lines, CD40 protected cells from apoptosis which was entirely dependent on the activation of NF-κB. In one of the FL cell lines, CD40 induced apoptosis itself. However, inhibition of NF-κB induced apoptosis in all three FL cell lines. Therefore, our results indicate that inhibitors of NF-κB or critical downstream anti-apoptotic targets of NF-κB instead of blocking CD40 antibodies in combination with TRAIL or other cytotoxic agents should be considered in the treatment of FL in order to prevent the protective effect of the microenvironment.