Introduction The purpose of the study was to compare three sequential pregnancies of American Indian women who have children with FAS or children with incomplete FAS with women who did not have children with FAS. Methods Two retrospective case-control studies were conducted of Northern Plains American Indian children with fetal alcohol syndrome (FAS) (Study 1) or incomplete FAS (Study 2) in 1981–1993. Three successive pregnancies ending in live births of 43 case mothers who had children with FAS, and 35 case mothers who had children with incomplete FAS were compared to the pregnancies of 86 and 70 control mothers who did not have children with FAS, respectively, in the two studies. Prenatal records were abstracted for the index child (child with FAS or incomplete FAS) and siblings born just before and just after the index child, and comparable prenatal records for the controls. Results Compared to the controls, significantly more case mothers used alcohol before and after all three pregnancies and during pregnancy with the before sibling and the index child. Mothers who had children with FAS reduced their alcohol use during the pregnancy following the birth of the index child. All Study 1 case mothers (100%) and 60% of Study 2 case mothers used alcohol during the pregnancy with the index child compared to 20 and 9% of respective control mothers. More study 1 case mothers experienced unintentional injuries (OR 9.50) and intentional injuries during the index pregnancy (OR 9.33) than the control mothers. Most case mothers began prenatal care in the second trimester. Conclusions Alcohol use was documented before, during and after each of the three pregnancies. Women of child-bearing age should be screened for alcohol use whenever they present for medical services. Mothers who had a child with FAS decreased their alcohol consumption with the next pregnancy, a finding that supports the importance of prenatal screening throughout pregnancy. Women who receive medical care for injuries should be screened for alcohol use and referred for appropriate treatment. Protective custody, case management and treatment services need to be readily available for women who use alcohol.