Hyperimmune rabbit and mouse sera raised to human herpesvirus 7 (HHV-7)-infected cells and an immune human serum identified 20[35S]methionine-[35S]cysteine-labelled proteins specific for HHV-7-infected cord blood mononuclear cells, ranging in apparent M(r) from 136K to 30K. The major proteins had apparent M(r) values of 121K, 100K, 87K, 85K, 60K, 51K, 46K, 42K, 40K and 36K. The human serum also identified seven [3H]glucosamine-labelled glycoproteins, with apparent M(r) values of 100K, 89K, 82K, 67K, 63K, 53K and 41K. Four monoclonal antibodies (MAbs) specific for HHV-7-infected cells were derived. Two reacted with a family of five antigenically related polypeptides (87K, 85K, 70K, 61K and 57K in apparent M(r)), designated as the p85 complex. Two reacted with 121K and 51K M(r) proteins designated as p121 and p51, respectively. Human sera react with high frequency with the p85 complex and to a lesser extent with p121; hence these two proteins appear to be immunodominant for both humans and laboratory animals. The hyperimmune mouse serum and some of the MAbs showed some cross-reactivity with HHV-6A(U1102)- and 6B(Z29)-infected cells. The implications of cross-reactivity with respect to the human immune response to HHV-6 and -7 infections and prevalence analyses are discussed.