Although arsenic (As), cadmium (Cd), lead (Pb), and nickel (Ni) have the ability to induce orofacial clefts (OFCs) in rodents, evidence is absent from human epidemiological investigations with markers of in utero exposure. We investigated the associations between concentrations of As, Cd, Pb, and Ni in umbilical cord tissues and risk of OFCs, and the interactions between each pair of metals on OFC risk in a case-control study. Umbilical cord concentrations of metals were determined by inductively coupled plasma mass spectrometry in 92 OFC cases and 200 nonmalformed controls. Concentrations above the median of all subjects was associated with an elevated OFC risk of 8.36-fold for As, 7.22-fold for Cd, 15.32-fold for Pb, and 6.79-fold for Ni. Concentrations of As, Cd, Pb, and Ni were also associated with risks for OFC subtypes. When metal concentrations were divided into tertiles by levels of metal concentrations of all subjects, dose-response relationships of risks for total OFCs and subtypes with As, Cd, Pb, and Ni concentrations were demonstrated. Significant synergistic interaction between As and Ni on the risk of OFCs was also observed. Therefore, elevated in utero exposure to As, Cd, Pb, and Ni may increase the risks of OFCs in newborns.