Galectin-3 (Gal-3) is an ubiquitous beta-galactoside-binding lectin implicated in cell growth, differentiation and apoptosis that plays an important role in inflammatory diseases. Here we report that B cells, with different functional behaviour, such as peritoneal B1 cells and conventional splenic B cells express similar levels of Gal-3 and that expression is 6.5-fold higher than T cells. Previously, we reported that Gal-3 expression increase during B cell differentiation to memory B cell whilst is almost null when B cells differentiate into antibody-secreting plasma cells (PC). To dissect possible mechanisms involved in Gal-3 downregulation, conventional purified splenic B cells were stimulated with LPS, which induces B cell differentiation to PC via TLR4. After 72 h of culture, LPS induced a strong decrease in Gal-3 expression determined at mRNA level by real time RT-PCR and at protein level by western blot. Immunofluorescence assays showed that PC presented a similar pattern of nuclear and citoplasmatic Gal-3 localization than resting B cell, although at a lower intensity. Blockade of RAS/MEK/ERK1/2 signalling with the PD98059 pERK inhibitor partially prevented Gal-3 dowregulation in LPS-stimulated B cells and reduced Ig release. Our results suggest that, during the differentiation of conventional B cells to PC Gal-3 is transcriptionally down-regulated through the RAS/MEK/ERK1/2 pathway.