Modification of beta-2-microglobulin has been shown to occur in vitro in serum of patients suffering of small cell lung cancer, where it clearly correlated to the clinical course of disease. The cause of serum beta-2-microglobulin modification occurring in these patients is investigated in the present study. This revealed that modification of beta-2-microglobulin is due to cleavage by a serine protease, which is dependent on divalent cations and has a trypsin-like specificity. The process showed the following characteristics: pH optimum at 8.5, heat inactivation by incubation at 56 degrees C for 20 min and temperature optimum at 20 degrees C.