Soluble histocompatibility antigen class I in breast cancer patients in relation to tumor burden. Serum beta-2 microglobulin (B-2M) levels were studied in 365 breast cancer patients and 210 age-matched controls. The patients were divided into three groups: Group A, new patients at diagnosis; Group B, patients at follow-up; and Group C, metastatic patients. The mean B-2M of all breast cancer patients plus or minus one standard deviation (3.5 +/- 1.2; range, 1.1 to 5.9) was significantly higher than normal controls (1.29 +/- 0.49; range, 0.3 to 2.3; P less than 0.005). When the three patient groups were compared with each other, the mean B-2M level of Group A (3.0 +/- 1.5; range, 0.9 to 6.9) was similar to that of Group C (4.22 +/- 1.1; range, 2.0 to 6.4). The mean B-2M of both Groups A and C was significantly higher than that of Group B (2.38 +/- 1.02, range, 0.4 to 5.4; P less than 0.001). In Group A the mean B-2M decreased significantly after a 12-month period and reached the mean level of Group B but not that of normal controls. When patients in Group B were analyzed by their stage of disease at diagnosis, there was no significant difference between Stages I and II. There was a significant difference in the mean B-2M levels between Stages I and III. In relapsing patients, mean B-2M levels increased. These findings suggest that serum B-2M levels may reflect tumor burden, and even in patients at follow-up, occult tumor cells may activate the immune system. 