The relationship of maternal illicit drug use to congenital syphilis was studied in a population of newborn infants (N = 1012) who were screened for intrauterine exposure to illicit drugs by meconium analysis and whose mothers were screened for syphilis by the rapid plasmin reagin fluorescent treponemal antibody, absorbed (RPR/FTA-ABS) test. The result of the meconium drug screening was positive in 449 (44.3%) infants: 401 (39.6%) screening results were positive for cocaine, 71 (7%) positive for opiate, and 31 (3.1%) positive for cannabinoid. The maternal RPR/FTA-ABS result was positive in 72 (7.1%) women, and congenital syphilis was diagnosed in 46 (4.5%) infants on the basis of Centers for Disease Control and Prevention definitions. The incidence of positive RPR/FTA-ABS result (10.5% vs 4.4%) and congenital syphilis (7% vs 2.5%) was significantly higher (p < 0.01) among infants with positive results compared with those with negative drug screening results. Similarly, the incidence of positive RPR/FTA-ABS (11% vs 4.6%) and congenital syphilis (8% vs 2.3%) was significantly (p < 0.01) higher among infants with cocaine-positive results compared with those with cocaine-negative results. We conclude that maternal illicit drug use, specifically cocaine, is significantly related to the resurgence of congenital syphilis among newborn infants.