In the past decade, large gains have been made in reducing pediatric HIV infections during the prenatal or peripartum period. However, recent changes in the World Health Organization (WHO) breastfeeding guidelines will likely shift the majority of new infant HIV infections to the postnatal period1,2. Although breastfeeding guidelines have changed, early infant diagnosis (EID) recommendations have not been updated. In this dissertation, I evaluated the performance of two HIV rapid tests, Determine and Unigold, on a cohort of 121 Malawian HIV-exposed, breast-fed infants who were HIV negative at 6 weeks postpartum from 3 to 18 months of age. I also evaluated the cost-effectiveness for several EID strategies that varied in type, timing, and number of rapid tests, including an Alere test, a point-of-care virological assay, through Markov modeling. Among 121 HIV-exposed infants, the estimated specificity increased quicker for Unigold to 100% (95% CI: 95.4, 100.0) by age 12 months compared with 95.6% (90.7, 100.0) by 15 months of age for Determine. Both tests failed to detect several incident HIV infections. Seroreversion occurred sooner with Unigold with an earlier mean time to seroreversion by 62 days (95% CI: 60, 64). Among 21 different EID strategies, the lowest costing strategy was testing once with Unigold at 9 months ($18.20 per infant) and testing twice with Alere at 6 and 15 months ($145.60 per infant). The strategies with the lowest and highest effectiveness were testing once with Unigold at 9 months (337,806 disability-adjusted-life years [DALYs]) and testing twice at 6 and 15 months with Alere (192,588 DALYs). After sequentially comparing all strategies in ranked order by costs, six remained cost-effective. Our findings highlight that the type and timing of rapid test matters greatly in regard to accurately identifying and ruling out pediatric HIV infections. Updated guidelines for use of rapid tests in young HIV-exposed children that explicitly takes the type of test and infant age into account are urgently needed to ensure optimal care for the 1.5 million HIV-exposed infants born annually, especially in light of the new breastfeeding guidelines.