By using a Lyme enzyme-linked immunosorbent assay (ELISA), we demonstrated that high ELISA index values are strongly predictive of Lyme disease. In children with clinical presentations consistent with Lyme disease, ELISA index values ≥3.0 had a positive predictive value of 99.4% (95% confidence interval: 98.1-99.8%) for Lyme disease, making a supplemental Western immunoblot potentially unnecessary.