We investigated the therapeutic effectiveness of monoclonal anti-idiotype (anti-M104E5) antibodies. Our in vitro studies show monoclonal anti-idiotype-specific antibody SJL 18-1 showed a selective inhibitory property for MOPC 104E cells over two cross-reactive idiotype antibodies N-20-2 (IgM, IdX-M104E, and J558) and CD3-2 (IgG1, IdX-M104E, and J558). Based on these observations, we further examined their biological activities in vivo. Mice given 2 x 104 MOPC cells s.c. were treated with various doses of the antibodies i.v. on days 0, 7, 14, 21, and 28 after tumor transplantation. In the group treated with 100 μg of N-20-2 antibody, the antibody treatment prevented the growth of MOPC 104E in some of the mice. Treatment of tumor-bearing mice with SJL18-1 antibody (10 to 1,000 μg/mouse) did not provide any survival benefit. On the other hand, in mice treated with 50 μg of CD3-2 antibody, four of ten mice had regression of their palpable tumors. It is important to note that the least effective antibody (CD3-2) in vitro was the most effective in vivo, and the most effective antibody (SJL18-1) in vitro did not show any survival benefit. Preliminary data indicate that the most likely mechanism of in vivo regulation of MOPC 104E myeloma is by cytostatic lymphocytes.