Elevated B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) serum levels have been reported to correlate with worse prognosis in B cell-derived malignancies. However, limited information exists regarding the prognostic significance of BAFF and APRIL serum levels in follicular lymphoma (FL). We measured BAFF and APRIL serum levels for 81 patients with newly diagnosed FL and 12 healthy controls. The mean ± standard deviation (SD) BAFF serum level (1,193.86 ± 1,126.51 pg/ml) was higher in patients with FL than that in the controls (477.16 ± 155.55 pg/ml; P < 0.001). No significant difference in the mean ± SD serum level of APRIL was found between patients and healthy controls (14.39 ± 43.33 vs 5.07 ± 2.52 ng/ml; P = 0.193). When the patients were divided into low- and high-BAFF and low- and high-APRIL groups based on the median value of the BAFF and APRIL serum levels (855.14 pg/ml and 6.35 ng/ml, respectively), a high APRIL, but not a high BAFF, serum level significantly correlated with low complete response rate to initial therapy, high relapse/progression rate, and inferior progression-free survival (PFS; P = 0.019) and overall survival (OS; P = 0.008) rates. A high APRIL serum level was also significantly associated with decreased PFS and OS in patients treated with non-rituximab regimens but not in patients treated with rituximab-containing regimens. The APRIL serum level remained an independent predictor for PFS and OS in multivariate analysis. APRIL may be an important prognostic predictor with potential significance as a therapeutic target in FL.