Mice treated from birth with rabbit anti-mouse IgM antiserum (anti-mu), although immunosuppressed in regard to B cell function, may paradoxically be protected when challenged with certain viruses. Our early studies indicated that short term treatment of weanling mice protected against Semliki forest virus, herpes simplex virus, and Coxsackievirus B1. For this study, the murine model of Coxsackievirus B1 infection was chosen to determine if specific anti-mu immunoglobulin (anti-mu Ig) would protect and whether protection could be correlated with antiviral activity in certain organs. Weanling Balb/c mice were treated intraperitoneally (i.p.) with either affinity purified anti-mu Ig or purified normal rabbit (NR) Ig two consecutive days prior to i.p. challenge with Coxsackievirus B1. Mortality of anti-mu Ig treated mice was significantly lower than controls (3.4% vs 89%, P less than 0.001). Importantly, this purified anti-mu-induced protection correlated well with reduced levels of virus in blood and certain organs, especially brain. This decrease was not attributed to interferon (IFN) or virus-specific neutralizing (NT) antibody or enhanced cellular cytotoxicity. Anti-mu treatment appears to inhibit virus replication and/or enhance clearance of virus from target organs. The data indicate that a unique antiviral activity is activated by anti-mu treatment, and can be passively transferred to and protect recipient mice. The murine model of Coxsackievirus disease appears to be well suited for use in the elucidation of the mechanism of this protection.