A comparison of direct antigen detection in cell scrapings with culture techniques (tube culture and shell vial method) for diagnosis of varicella-zoster virus (VZV) mucocutaneous infections was done in parallel in two groups of specimens. A total of 100 specimens were from patients with clinical diagnosis of VZV infection (group 1), and 69 were from patients with no suspicion of VZV infection (group 2) but mainly with herpes simplex virus infections. In addition, three commercially available monoclonal antibodies (Whittaker, Biosoft Clone 2013, and Ortho 3B3) directed against VZV antigens were evaluated in parallel in the last 87 group 1 specimens. Overall, 80% of the group 1 specimens were confirmed positive by direct detection, in comparison with 56% positive by tube culture and/or shell vial. None of the group 2 specimens were positive for VZV by any of the methods, and none of the monoclonal antibodies assayed reacted with any herpes simplex virus stock strains. Antiviral therapy and the length of evolution time of lesions affected negatively the performance of all laboratory methods, but to a lesser extent in direct detection techniques than in culture techniques. The Whittaker and Biosoft reagents (indirect immunofluorescence assay) showed statistically significant differences in sensitivity with respect to the Ortho antibody (P = 0.002 and P = 0.039, respectively; two-tailed binomial test). Direct antigen detection is a rapid, easy-to-perform, sensitive, and specific technique and appears to be the method of choice for laboratory confirmation of VZV mucocutaneous infections.