Streptococcus pneumoniae colonizes the nasopharynx of healthy human carriers, but occasionally can spread in the body causing severe diseases. The mucosa of the respiratory tract is enriched in mast cells, key players of the innate immune response. Here, we report on the interaction of various strains of S. pneumoniae with the mast cell line RBL-2H3. Live, but not heat-killed, bacteria were found to induce mast cell degranulation in a dose- and time-dependent manner, only partially controlled by cytosolic calcium, with no production of TNF-alpha and IL-6. Non-encapsulated pneumococcal strains exhibited different potencies in triggering mast cells. We propose here that the induction of mast cell degranulation by pneumococcal factors not accompanied by the production of pro-inflammatory cytokines may be a specific strategy elaborated by this bacterium to promote its own spreading from the respiratory mucosa into the environment.