Cluster headache is a primary headache with prevalence of 0.1%. We found no literature data on valacyclovir therapy in patients with chronic recurrent herpes-virus infection and concomitant chronic cluster headache. We report a 27-year-old patient with severe headache for previous 10 years. Incidence of headaches was up to 7 times per a week without remissions. At the same time, the patient suffered from labial/nasal form of chronic recurrent herpes virus infection (Herpes simplex) for a long time. Recurrence rate was up to 6 times a year (severe course). According to the European and Russian clinical guidelines, we have prescribed valacyclovir 1000 mg per a day since January 28, 2020. On January 29, 2020, the patient experienced another attack of cluster headache with ineffective therapy. Headache persisted for 2 hours that required invasive analgesia (blockade of the pterygopalatine ganglion). Three hours later (5 hours after clinical manifestation), headache regressed. On January 31, 2020, the patient experienced severe headache again. Redo blockade of pterygopalatine ganglion resulted earlier regression of headache (4 hours after onset of attack and 1 hour after blockade). Valacyclovir was canceled after February 2, 2020, and there were no subsequent recurrences of attacks. After that, the patient had typical attacks of chronic cluster headache. Correction of verapamil therapy was carried out. After some time, long-term remission of chronic cluster headache was achieved at daily dosage of verapamil of 480 mg. Combination of diseases is a common situation in clinical practice requiring careful selection of therapy and assessment of its interaction and tolerability. Thus, acyclovir in standard doses should be preferred in patients with chronic cluster headache requiring acyclic nucleosides. Combination with other alternative methods of treatment (immunotherapy) may be advisable since valacyclovir may aggravate the course of chronic cluster headache.