The molecular basis for the high survival rate of rainbow trout, Oncorhynchus mykiss, infected with furunculosis was investigated. 2. Alpha 2-macroglobulin (alpha 2M), a major serum protease inhibitor, was partially purified from rainbow trout and brook trout, Salvelinus fontinalis, sera; the latter species shows marked disease susceptibility. 3. It is shown that a 10-fold species-based difference in alpha 2M inhibitory activity exists against a furunculosis associated bacterial protease. 4. A possible basis for the observed disparity is discussed. 5. Results suggest that the high mol. wt form of teleost (trout) albumin is a dimer composed of two 85,000 subunits.