The Oka varicella vaccine strain can be differentiated from wild-type strains by its unique restriction endonuclease fingerprinting (REFP: HpaI-K and EcoRI-P) pattern of the gpV-coding region of the varicella-zoster virus (VZV) genome. VZV-DNAs from patients with complicated clinical courses related to vaccination were examined to determine whether they were vaccine-derived or wild-type. A virus was isolated from a one year-old boy with acute lymphocytic leukemia (ALL) who developed typical varicella 28 days after vaccination (case A). Another virus was isolated from a four-year-old boy without clinical symptoms following household contact with varicella patients at the age of two months, and he developed zoster 14 months after vaccination (case B). Also, two strains (OK1 and OK2) were isolated from household contacts (mother and sister) with a vaccine with ALL in Oklahoma who developed varicella 18 days after vaccination (case C). In case C, BgII-REFP did not determine conclusively whether the two strains (OK1 and OK2) were vaccine-derived or wild-type because the patterns obtained were different from both the Oka varicella vaccine strain and American wild-type strains [Gelb et al., Journal of Infectious Diseases, 155:633-640, 1987]. All VZV strains examined in the present study were identified as wild-type by our method using HpaI-K and EcoRI-P fragments as marker fragments. Thus it is becoming evident that REFP using HpaI and EcoRI endonucleases is a convenient and reliable means of distinguishing between the Oka vaccine virus strain and wild-type viruses isolated from individuals developing vesicular rashes shortly and long after varicella vaccination.