The absence of markers of inflammation in the cerebrospinal fluid (CSF) commonly predicts the absence of herpes simplex virus (HSV) central nervous system (CNS) infection. Consequently, multiple authors have proposed and validated criteria for deferring HSV PCR testing of CSF in immunocompetent hosts with normal CSF white blood cell and protein levels (Յ5 cells/mm 3 and Յ50 mg/dl, respectively). Hosts are considered immunocompetent if they are Ն2 years old and have not had HIV or an organ transplant. Adoption of the criteria may erroneously exclude HSV-infected persons from a necessary diagnostic test or, alternatively, reduce the costs associated with HSV tests with minimal to no effect on patient care. Little is known about the cost-effectiveness of this approach. A decision analysis model was developed to evaluate the adoption of criteria for screening HSV tests of CSF. Estimates of input parameter values combined available literature with a multiyear multisite review at two of the largest health care systems in the United States. Adoption of criteria to screen for HSV test need proved cost-effective when less than 1 in 200 patients deferred from testing truly had an HSV CNS infection. Similar to prior studies, none of the deferred cases had HSV encephalitis (n ϭ 3120). Adoption of these criteria in the United States would save an estimated $127 million ($95 million to $158 million [Ϯ25%]) annually. The model calculations remained robust to variation in test cost, prevalence of HSV infection, and random variation to study assumptions. The adoption of criteria to screen HSV PCR tests in CSF represents a cost-effective approach.KEYWORDS cost-effectiveness, herpes simplex virus, polymerase chain reaction M ultiple studies have identified herpes simplex virus (HSV) as the most common cause of encephalitis (1-3). Unlike treatment of other causes of viral encephalitis, treatment of herpes simplex virus with acyclovir (ACV) has the highest recommendation for treatment from the Infectious Diseases Society of America (4). The combination of relatively benign treatment and a poor prognosis without treatment justifies a laboratory workup for many more patients than have the disease. The gold standard test for herpes simplex has become nucleic acid amplification, such as HSV PCR. An alternative approach to PCR proposes to test only select patients who meet specific clinical and laboratory criteria.Over the past 15 years, evidence for excluding herpes simplex virus without HSV PCR has accumulated (5-10). The authors of these studies cited five primary factors as their motivation. First, the spectrum of disease detected by PCR has become less severe and less treatable (e.g., Mollaret's meningitis, HSV-2 meningitis) (11). Second, PCR for HSV has a very low positive rate, between 1% and 3%. Most of the positive results are not