In immunocompetent patients, HSV is controlled rapidly by the human host's immune system, and recurrent lesions are small and short lived. When treated with antiviral agents, these patients rarely develop resistance to these drugs. In contrast immunocompromised patients might not be able to control HSV infection. Thus, frequent and severe reactivations are often seen and might lead to fatal herpetic encephalitis or disseminated HSV infection. Treatment in these patients is limited because immunocompromised hosts often develop severe herpes disease refractory to antiviral drug therapy. It is therefore imperative that physicians develop regimens to deal with both receptive and refractory HSV disease. The following treatment protocol (modified from Balfour and colleagues) might serve as a guide until further investigation of new drugs is performed. In all patients standard oral ACV therapy should be initiated at a dose of 200 mg orally, five times a day for the first 3 to 5 days. Prior to treatment, cultures the lesions should be obtained to verify HSV etiology. If the response is poor, the dose of oral ACV should be increased to 800 mg five times a day. If no response seen after 5 to 7 days, it is unlikely that the lesion will respond to intravenous ACV (or chemically and structurally related drugs such as VCV or famciclovir), so an alternative regimen must be assigned. First, repeat cultures for vital, fungal, and bacterial pathogens must be performed. In addition, ACV susceptibility studies should be ordered, if available. If the mucocutaneous lesion is accessible for topical treatment, TFT (as ophthalmic solution) should be applied to the area three to four times a day until the lesion is completely healed. If the lesion is inaccessible or if the response to TFT is poor, therapy with intravenous foscarnet should be given for 10 days or until complete resolution of the lesions. The dosage of foscarnet should be 40 milligrams per kilogram three times per day or 60 milligrams per kilogram twice daily. If foscarnet fails to achieve clinical clearing, consideration should be given to use of intravenous cidofovir (or application of compounded 1% to 3% topical cidofovir ointment). Vidarabine is reserved for situations in which all of these therapies fail. If lesions reoccur in the same location following clearing, the patient should started on high-dose oral ACV (800 mg, five times daily) or intravenous foscarnet (40 mg/kg tid or 60 mg/kg bid) as soon as possible. When lesions occur in a different location, the patient should be treated initially with standard doses of oral ACV (200 mg, five times daily) and the above protocol should be followed should there be clinical failure. In the future, new treatment options for patients with documented HSV resistance will be important in reducing the clinical impact of HSV.