Vaccinia virus recombinants containing herpes simplex virus (HSV) type 1 (VP176) or type 2 (VP221) glycoprotein D (gD) genes were studied for their protective potential in the guinea pig model of recurrent HSV type 2 disease. Cells infected with these recombinants synthesized at least one protein (precursor, mature form, or both) that was precipitated with monoclonal antibody to HSV type-common determinants on gD. These determinants were detected on the surface of cells infected with the recombinants at 2 hr after infection. VP176 immunization protected against primary (P ⪡ .001) and recurrent (P ⪡ .001) cutaneous HSV type 2 lesions and ganglionic latency (62% protection). VP221 immunization protected against recurrent disease (P < .05), although HSV type 2 gan-glionic infection was established. Protection, first observed at two weeks after immunization, apparently did not involve HSV-specific neutralizing antibody because seroconversion was detected at 35–45 days after immunization. Protection was correlated with HSV-specific lymphoproliferation and the elaboration of lymphokines that enhance natural killer cell cytolysis.