Background and Objective: Above 90% of childhood HIV infections result from mother-to-child transmission (MTCT). This study examined the MTCT rates of HIV-exposed infants enrolled in the infant follow-up arm of the prevention of mother-to-child transmission (PMTCT) program in a teaching hospital in Southeast Nigeria. Methods: This was a 14-year review of outcomes of infants enrolled in the infant follow-up arm of the PMTCT program of Nnamdi Azikiwe University Teaching Hospital Nnewi, Nigeria. The majority of subjects were enrolled within 72 hours of birth and were followed up until 18 months of age according to the National Guidelines on HIV prevention and treatment. At enrollment, relevant data were collected prospectively, and each scheduled follow-up visit was recorded both electronically and in physical copy in the client’s folders. Data were analyzed using SPSS version 20. The major outcome variable was final MTCT status. Results: Out of 3,784 mother-infant dyads studied 3,049 (80.6%) received both maternal and infant Antiretroviral (ARV) prophylaxis while 447 (11.8%) received none. The MTCT rates were 1.4%, 9.3%, 24.1%, and 52.1% for both mother and infant, mother only, infant only, and none received ARV prophylaxis respectively. There was no gender-based difference in outcomes. The MTCT rate was significantly higher among mixed-fed infants (p<0.001) and among those who did not receive any form of ARVs (p<0.001). Among dyads who received no ARVs, breastfed infants significantly had a higher MTCT rate compared to never-breastfed infants (57.9% vs. 34.8%; p<0.001). The MTCT rate was comparable among breastfed (2.5%) and never-breastfed (2.1%) dyads who had received ARVs. After logistic regression, maternal (p<0.001, OR: 7.00) and infant (p<0.001, OR: 4.00) ARV prophylaxis for PMTCT remained significantly associated with being HIV-negative. Conclusion and Global Health Implications: Appropriate use of ARVs and avoidance of mixed feeding in the first six months of life are vital to the success of PMTCT programs in developing countries. PMTCT promotes exclusive breastfeeding and reduces the burden of pediatric HIV infection, thereby enhancing child survival.