OBJECTIVE The purpose of this study was to examine birth outcomes in women treated or untreated for thrombophilia during pregnancies affected or not by tobacco exposure. METHODS This was a retrospective cohort study of consecutive women from a single maternal fetal medicine clinic who delivered between January 2009 and December 2013. We compared birth outcomes by four groups of thrombophilia and smoking combinations and then by treated or untreated groups. RESULTS Of the 8889 pregnant women in this study, 113 had thrombophilia and 97 received treatment. Thromboprophylaxis included: low molecular weight heparin, aspirin, unfractionated heparin, folic acid, and combinations of these. Smokers with thrombophilia had significantly higher rates of preeclampsia, intrauterine growth restriction, preterm birth (<37 weeks gestation) and low birth weight (all p ≤ .001). Conversely, this group had significantly lower rates of hemolysis, elevated liver enzymes, low platelet count (HELLP syndrome) and placental abruption. Women with thrombophilia who received thromboprophylaxis had lower rates of adverse birth outcomes, reaching significance for preterm birth <32 weeks gestation (4.3% versus 21.1%, p = .026). CONCLUSION Pregnant women who smoke and have thrombophilia may be more likely to experience adverse birth outcomes and receive more benefit from thromboprophylaxis than their nonsmoking counterparts.