The acute phase members of the mouse serum amyloid A (Saa) family, Saa1, Saa2 and Saa3, are highly similar at both the nucleotide and protein sequence levels. Saa1 and Saa2 in the BALB/c strain are 72% identical over the first 500 bp upstream of their transcription start sites and to date have been considered to be coordinately regulated. Furthermore, based on their homology with the upstream regions of the human SAA1 and SAA2 genes, it has been assumed that they are Type I acute phase proteins (APPs), i.e. they are primarily regulated by IL-1 and TNF. Here we establish that the BALB/c Saa1, Saa2 and Saa3 genes, in fact, respond differently to IL-1, TNF and IL-6. The Saa1 and Saa2 promoters are strongly induced by IL-6, with synergistic upregulation of Saa2, but not of Saa1, by IL-1 or TNF. In contrast, the Saa3 promoter is strongly induced by IL-1, moderately induced by TNF and only minimally induced by IL-6. We also define important sequence differences between the Saa promoters of Type A (BALB/c and ICR/Swiss) and Type B (129/Ola) strains of mice, that have dramatic qualitative and quantitative consequences for Saa1 and Saa2 regulation. These findings mandate careful strain selection prior to embarking on studies involving mouse models of secondary amyloidosis or cytokine inactivation.