We analyzed the prognostic impact of levels of free light chains (FLC) in 106 patients with DLBCL, selecting 61 patients with a monoclonal (M) protein in serum, and 45 patients without a M protein as an IPI-matched control group. Patients with a M protein had higher levels of FLC, but these were not of prognostic significance in this group. The presence of a M protein nullified associations of κ-FLC with several laboratory parameters indicating immune system activation observed in patients without a M protein. Patients without M protein and κ-FLC >50 mg/L had a significant inferior event-free survival (p = .004). The presence of M protein of an IgM type at diagnosis was a negative outcome predictor (p = .008), while a non-IgM M protein did not significantly impact on prognosis. In conclusion, the prognostic performance of the FLC assay is altered by the presence of a M protein.