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BACKGROUND AND OBJECTIVE: To determine the diagnostic yield of systemic work-up in white dot syndromes. PATIENTS AND METHODS: A retrospective chart review. RESULTS: Eighty-six consecutive patients with a diagnosis of a white dot syndrome were identified. Forty-three had a diagnosis of birdshot chorioretinopathy. Overall, 395 diagnostic tests were performed with a diagnostic yield of 11.9%. The test with the greatest diagnostic yield was HLA-A29 typing (89%). Four patients had abnormal angiotensin converting enzyme levels. No patients had a positive rapid plasma reagin or fluorescent treponemal antibody absorption test. Four patients had positive tuberculosis testing and required treatment. The mean number of tests performed per diagnosis group ranged from 0.3 in multiple evanescent white dot syndrome to 5.6 in multifocal choroiditis and panuveitis. Diagnostic testing was found to be the most expensive in birdshot chorioretinopathy, with a mean cost of $504.82. CONCLUSIONS: Diagnostic yield of systemic work-up was low in this patient population. Rather than performing an exhaustive work-up, the authors advocate for a limited work-up tailored to pretest clinical suspicion. [ Ophthalmic Surg Lasers Imaging Retina . 2017;48:540–545.]