Serum amyloid A (SAA) is a precursor for the amyloid A in AA type of amyloidosis. Distribution of mast cells in tissues is similar to the distribution of amyloid deposits in secondary AA-amyloidosis. Therefore, we studied whether mast cells could be involved in SAA metabolism. Human mast cell line (HMC-1) cells were cultured with recombinant human apoSAA (rhSAA), and the production of tumour necrosis factor (TNF)-alpha and interleukin (IL)-1 beta was determined by ELISA. RhSAA and human SAA (huSAA) were incubated with human chymase, tryptase or with intact human mast cell (huMC) in cultures, and degradation of SAA was followed by gel electrophoresis, liquid chromatography and mass spectrometry. SAA induced dose-dependent production of TNF-alpha and IL-1 beta in HMC-1 cells. Tryptase, chymase, and huMC granules degraded efficiently the SAA protein. Degradation of SAA by tryptase, but not by chymase, released a highly amyloidogenic N-terminal fragment of SAA. Finally, incubation of huMC with rhSAA alone resulted in degradation of SAA and formation of protofibrillar intermediates. These results suggest a pathogenic role for mast cells in AA-amyloidosis.