The detection of IgG oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is, as yet, the recommended biochemical marker for the diagnosis of multiple sclerosis (MS). Aim of this study was to investigate the behaviour of free light chains (FLC) in OCBs negative (OCBs-) MS patients compared with that in OCBs positive (OCBs + ) MS patients and in a control group (CG) of subjects without cerebrospinal inflammatory disease. At multiple comparisons between the three groups, statistically significant differences (p < .001 for all) were found for kappa FLC. Conversely, lambda FLC values evidenced a greater overlapping in the three groups. Receiver operating characteristics (ROC) curves made with kappa FLC values, evidenced the greater differences of areas under curves (AUCs) between OCBs- and OCBs + (AUCs: kappa FLC 0.98, Q kappa FLC 0.98, kappa FLC index 0.96) with respect to the differences between OCBs- and CG (AUCs: kappa FLC 0.77, Q kappa FLC 0.86, kappa FLC index 0.77): indeed > 50% of MS OCBs- subjects studied evidenced the same values of kappa FLC, Q kappa FLC and kappa FLC index found in CG. Conversely, if the aim is to select MS subjects while avoiding undertaking the more complex isoelectrofocusing test, values with absolute specificity for MS (Q kappa FLC = 15, sensitivity = 0.76 and kappa FLCindex = 3.09, sensitivity = 0.72) could be used. The values found in this study call for confirmation with data from more subjects, including those with other CSF inflammatory diseases. Anyway, the most important finding was that, for some OCBs- subjects, kappa FLC are more effective than OCBs in diagnosing MS.