As chronic lymphocytic leukemia (CLL) has a variable disease course, novel prognostic markers and risk assessment models are being developed in order to identify high-risk patients who may need early treatment. The two tumor necrosis factor family proteins BAFF and APRIL and their receptors BAFF-R, TACI and BCMA are considered to play a critical role in the survival of normal B cells. In order to highlight the pathophysiological role of this complicated biological network, we aimed to analyze the potential prognostic effects of BAFF, APRIL, TACI and BCMA in CLL patients. We investigated the prognostic impact of serum BCMA, TACI, BAFF and APRIL levels in 129 newly diagnosed CLL patients [median age: 64 (39-88) years; male/female: 85/44]. Serum BAFF, TACI and BCMA levels were significantly lower in the patient group compared to the control group (p<0.001), while serum APRIL level did not differ significantly between two groups (p>0.05). Serum BCMA [(p=0.029; r=0.208)] and TACI levels [(p=0.011; r=0.241)] were positively correlated with serum free light chain ratio. Serum BAFF [(p=0.008; r=-0.236)] and BCMA [(p=0.042; r=-0.183)] levels were negatively correlated with Rai stage. Overall survival (OS) was relatively better in patients with low serum BAFF levels [60 (1-187) months vs 39.5 (0-256) months; p=0.063]. Probability of OS was higher in patients with low BAFF levels when compared to patients with normal levels, without statistical significance (53.6% vs 23.6%; p>0.05). Large prospective studies are needed to validate the prognostic role of this essential biological pathway in CLL.