We studied the clinical resistance to acyclovir of infections with varicella-zoster viruses (VZV) in patients with acquired immunodeficiency syndrome, and we correlated it to virologic analyses. Eleven patients with VZV infections (treated with acyclovir, 30 mg/kg/day, given intravenously, or 4 g/day, given orally) were included in the study because of the failure of 10 days of acyclovir therapy. Susceptibility of VZV isolates to acyclovir was tested using a plaque reduction assay to determine the 50% inhibitory concentration (IC(50)) of acyclovir and the SI(50) (IC(50) of the patient isolate/IC(50) of the reference strain) to acyclovir. The thymidine kinase (TK) gene, which supports the resistance, was sequenced on amplified products. Only 3 patients had a significant increase in the IC(50), as compared with the IC(50) of the reference strain (SI(50) of > or =4), and a mutation in the TK gene. For the other 8 patients, the clinical resistance was not confirmed by the virologic results: the SI(50) was < 4, and no mutation was detected in the TK gene. Because no acyclovir-resistant strain appeared during a shorter period of time, we suggest an increase in the duration of the treatment to 21 days before acyclovir resistance is suspected.