BACKGROUND: Retinal imaging with remote interpretation could decrease the number of diagnostic eye examinations that premature infants need for the detection of retinopathy of prematurity and thus decrease the time demand on the relatively small pool of ophthalmologists who perform retinopathy of prematurity examinations. OBJECTIVE: Our goal was to review systematically the evidence regarding the reliability, validity, safety, costs, and benefits of retinal imaging to screen infants who are at risk for retinopathy of prematurity. METHODS: We searched Medline, the Cochrane library, CINAHL, and the bibliographies of all relevant articles. All English-language studies regardless of design with primary data about our study questions were included. We excluded (1) studies that only included subjects with retinopathy of prematurity, (2) hypothetical models other than cost-effectiveness studies, and (3) validity studies without sufficient data to determine prevalence, sensitivity, and specificity or that only evaluated subjects for 1 component of retinopathy of prematurity (eg, plus disease only). RESULTS: Studies of only 1 retinal imaging device (RetCam [Clarity Medical Systems, Inc, Pleasanton, CA]) met the inclusion criteria. There was a wide range in reported sensitivity, but specificity was high. There were several important limitations noted, including the eye as the unit of analysis instead of the individual or variations in the criteria for determining a true-positive or true-negative screening result. The risk of retinal hemorrhage resulting from imaging is low, and systemic effects (eg, bradycardia, hypertension, decreased oxygen saturation) are mild. No generalizable cost-effectiveness data were found. CONCLUSIONS: The evidence base is not sufficient to recommend that retinal imaging be routinely adopted by NICUs to identify infants who have serious retinopathy of prematurity.