Nonspecific reactions to the membrane antigen of varicella-zoster virus were found by fluorescent antibody assay in the sera of three children susceptible to the virus; one of these children subsequently developed varicella. None of the three sera, however, contained antibody to varicella-zoster virus that was detectable by enzyme-linked immunosorbent assay (ELISA). Moreover, the results of the ELISA clearly distinguished immune from susceptible individuals. The negative range was established with sera obtained from 15 individuals prior to the onset of varicella, and the positive range was established with sera obtained from 75 healthy donors with a history of varicella. The results of the ELISA correlated well with those of the fluorescent antibody assay (r = +0.84). Heterologous reactions to herpes simplex virus were found in one of seven sera tested, and such reactions to cytomegalovirus were found in two of five sera. Heterologous reactions to Epstein-Barr virus were found in none of eight sera tested. ELISA is easy, sensitive, and reproducible and can be used for routine screening for susceptibility to varicella.