OBJECTIVE: To explore the role of folic acid supplements, dietary folates, and multivitamins in the prevention of facial clefts. DESIGN: National population based case-control study. SETTING: Infants born 1996-2001 in Norway. PARTICIPANTS: 377 infants with cleft lip with or without cleft palate; 196 infants with cleft palate alone; 763 controls. MAIN OUTCOME MEASURES: Association of facial clefts with maternal intake of folic acid supplements, multivitamins, and folates in diet. RESULTS: Folic acid supplementation during early pregnancy (> or =400 microg/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96). Independent of supplements, diets rich in fruits, vegetables, and other high folate containing foods reduced the risk somewhat (adjusted odds ratio 0.75, 0.50 to 1.11). The lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins (0.36, 0.17 to 0.77). Folic acid provided no protection against cleft palate alone (1.07, 0.56 to 2.03). CONCLUSIONS: Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third. Other vitamins and dietary factors may provide additional benefit.