Early immune response was studied by assessing interferon (IFN) and natural killer cell activity in 13 patients with exanthem subitum associated with human herpesvirus 6 infection during the acute and convalescent phases. Only IFN-alpha showed a significant increase in the plasma of patients during the acute febrile phase compared with the convalescent period. The inhibitory effect of IFN-alpha and IFN-beta on human herpesvirus 6 replication was demonstrated in vitro with cord blood mononuclear cells. Natural killer cell activity was also significantly augmented in the acute phase, especially in the exanthem period, rather than in the convalescent phase (P less than 0.01). These results suggest that the enhanced IFN-alpha response and natural killer cell activity in the acute early phase of the disease may play pivotal roles in the recovery from exanthem subitum.