Summary: Eight strains of herpes simplex virus, recently isolated from a variety of human sources, were compared to three well-established reference strains. Both egg-adapted and mouse-adapted lines of these viruses were studied in cross-neutralization and cross-protection tests. While there was considerable uniformity in the immunological reactions of all strains, some could be differentiated from the rest. When compared to the reference strain HF, at least two strains showed antigenic differences in excess of 50% by the constant virus-serum dilution technique of neutralization tests in mice. These “atypical” herpes viruses did not resemble one recently isolated strain of B virus. It is concluded that in spite of the relative antigenic uniformity of herpes viruses, differences in immunological behavior can be demonstrated with occasional strains. The nature of these differences is discussed.