For determination of whether the Fc moiety is required for antibody effectiveness in models of herpes simplex virus type 1 (HSV-1) infection, the effects of immune IgG and F(ab')2 fragments were compared by using a passive transfer model of footpad infection. In the IgG- and the F(ab')2-treated groups illness developed in 2 (10%) of 20 and 6 (25%) of 24 mice, respectively, compared with 10 (63%) of 16 controls. IgG treatment markedly, and F(ab')2 treatment moderately, reduced footpad viral titer and viral spread to sciatic nerve and spinal cord. The marked viral clearance by IgG was not attributable to C'-dependent lysis because rapid viral clearance was observed in C5-deficient B10.D2/oSn mice. Viral latency as a consequence of acute infection occurred in 38 (63%) of 60 lumbosacral dorsal root ganglia in the control group, 5 (8%; P less than .001) of 60 in the IgG-treated group, and 26 (33%; P less than .01) of 78 in the F(ab')2-treated group.