OBJECTIVE The aim of this study was to evaluate the accuracy and clinical usefulness of a new computer-driven, hand-held device (Chromatics Colormate III) to estimate serum bilirubin from skin-reflectance (skin color) of neonates. METHODS A total of 2441 infants (both term and premature) at two hospitals had repeated measurements of transcutaneous bilirubin. Of these infants, 900 had one or more laboratory determinations of serum bilirubin. Many of the infants had early measurements of skin color before the onset of jaundice. A visual estimate of the degree of jaundice was made by a health care worker when the laboratory study was drawn. A subgroup of 61 infants was also studied while undergoing phototherapy with a total of 284 comparisons obtained. The reproducibility of the instrument was assessed separately using standardized color tiles and repeated measurements by multiple operators. RESULTS The range of serum bilirubin measurements that had concurrent skin color measurements was 3.22 to 338.1 micromol/L (0.2 to 21 mg/dL). The linear regression indicated an r = 0.956, and 95% of the skin color measurements were within 32.2 micromol/L (2.0 mg/dL). There was no interference with the accuracy of the device because of infant race or weight, or because of the use of phototherapy. The device provided reproducible information when infants were tested repeatedly over 30 minutes; the coefficient of variation for the transcutaneous bilirubin measurement was 3.1% around a mean estimate of 135.32 micromol/L (8.4 mg/dL). CONCLUSIONS The Chromatics Colormate III allows for a clinically useful estimate of serum bilirubin in a wide variety of infants. By using a color discrimination algorithm and obtaining a skin measurement before the onset of icterus, this instrument can provide valuable clinical information that obviates the need for serum bilirubin determinations. Its use in newborn nurseries may allow physicians to shorten length of stay more safely and decrease the use of invasive blood tests.