Psychiatric side-effects associated with acyclovir therapy are very rare in the medical literature. We present a case of depression with paranoid delusions in a patient with chronic lymphocytic leukemia that appeared after intravenous acyclovir treatment for herpes simplex infection. The clinical picture resolved following discontinuation of acyclovir and treatment with haloperidol and maprotiline. The patient's status was intact at an eight-month follow-up check. The few reports of psychiatric disorders due to acyclovir are reviewed and discussed.