This study aimed to identify factors contributing to high rates of preterm birth (PTB), low birth weight (LBW) and infant mortality in Mississippi while considering both traditional risk factors and maternal medical conditions. The retrospective cohort study used 1996–2003 Mississippi linked birth and infant death files. Multiple logistic regression was used to investigate association between maternal medical conditions and unfavorable birth outcomes. Along with traditional risk factors, hypertension was significantly associated with PTB and LBW. Women with hypertension were about 2.2 and 3.2 times as likely to have PTB and LBW, respectively. Hydramnios/oligohydramnios increased 1.8–4.4 folds of risk for PTB, LBW and infant death and was significantly associated with the unfavorable birth outcomes. Non-Hispanic black women were about 1.5–2.0 times as likely to have an unfavorable birth outcome compared to non-Hispanic white women. Maternal education and prenatal care effect appeared to be modified by maternal race. Certain maternal medical conditions may be contributing to PTB, LBW and infant mortality rates identifying preconception and prenatal healthcare as possible strategies for reducing unfavorable outcomes. Results suggest that different risk profiles for unfavorable outcomes may exist according to maternal race highlighting the need to consider racial groups separately when further exploring the sociodemographic and/or health-related factors that contribute to unfavorable birth outcomes.