Despite the known dangers of pregnancy smoking, rates remain high, especially in the rural, Southern United States. Interventions are effective, but few have been developed and tested in regions with high rates of pregnancy smoking, a culture that normalizes smoking, and a hard-to-reach prenatal population. The goals were to describe a smoking cessation intervention, the Tennessee Intervention for Pregnant Smokers program, and examine the impact on quit rates compared to usual care. Additionally we sought to examine reduction in smoking levels and number of quit attempts related to the intervention and finally to examine the impact of the intervention on birth outcomes. Intervention and historical control group participants, all smokers at entry to prenatal care, were recruited from five medical practices providing prenatal care in rural, South-Central Appalachia. The intervention, an expanded 5A’s (Ask, Advise, Assess, Assist, Arrange) model, was delivered by trained health educators. Over 28% of intervention group women quit smoking, compared to 9.8% in the control group. Two thirds of intervention group women significantly reduced smoking by delivery, with 40%+ attempting to quit at least once. Compared to controls, intervention group women saw significantly better birth outcomes, including newborns weighing 270g more and 50% less likely to have a neonatal intensive care unit admission. Among intervention group participants, those who quit smoking had significantly better birth outcomes than those who did not quit smoking. Findings point to the potential for appropriately tailored pregnancy smoking interventions to produce substantial improvements in birth outcomes within populations with health disparities.