Over a 3-month period, four patients who had received unrelated donor (UD) bone marrow transplants (BMT) presented with severe mucocutaneous herpes simplex virus (HSV) infection while receiving acyclovir (ACV) prophylaxis. Sensitivity testing of the isolates revealed three to be acyclovir-resistant and in one patient the infection was also characterised by a marked failure to respond to foscarnet (phosphonoformic acid). The emergence of ACV-resistant HSV infections in themselves is a new and challenging problem, and yet a far greater problem will become evident if these infections develop resistance to non thymidine kinase dependent therapy.