A case of herpes simplex virus (HSV) encephalitis with disseminated primary HSV infection in a renal transplant patient is described. The diagnosis of the disease was achieved by nested polymerase chain reaction (PCR)-DNA in cerebrospinal fluid (CSF). Other diagnostic measures (immunoglobulin [Ig] M and virological cultures both in blood and CSF) were negative. Blood IgG gave a false-positive signal. Although ganciclovir is not the drug of choice, its concomitant administration in our patient as a prophylactic measure against CMV infection may have decreased the usual severity normally expected in this kind of primary HSV infection. The subsequent increase in ganciclovir dose to full therapeutic range, which was implemented before the diagnosis was achieved, led to the disappearance of symptoms. The detection of PCR-DNA in CSF will probably become the diagnostic method of choice. One of its great advantages, in addition to its diagnostic reliability, is that it may obviate the performance of many cerebral biopsies.