We evaluated varicella-zoster virus (VZV) culture and serum antibody methods utilizing specimens from 620 children enrolled in protocols for prevention or treatment of varicella and samples routinely submitted to the Clinical Virology Laboratory. In a foreskin fibroblast tube culture system, we initially isolated VZV from only 29 (51%) of 57 children cultured on the first day of varicella. After modifying the method, the proportion of culture-positive children increased significantly to 36 (80%) of 45 (p less than 0.005 by corrected X2), and the median days-to-positivity were significantly shortened from 5.6 to 3.8 days (p less than 0.001, Wilcoxon rank-sum test). The Viran fluorescent antibody to membrane antigen (FAMA) assay was difficult to read and not reproducible. The standard FAMA was more sensitive than the Merck ELISA antibody test for detecting vaccine-induced antibody. The Whittaker ELISA did not detect vaccine-induced antibody but was comparable to FAMA for immune status testing (sensitivity, 95%; specificity, 92%) and for diagnosis of acute varicella.