Background: Despite the effectiveness of antiretroviral therapy, vertical HIV transmission continues. A potent, broadly neutralizing, monoclonal antibody (bNAb) administered to HIV-exposed infants might reduce transmission. VRC07-523LS is 5-fold more potent and has a prolonged half-life compared to VRC01. VRC07-523LS may provide therapeutic levels over the duration of breastfeeding with infrequent doses. Methods: This is an open-label study of VRC07-523LS administered to HIV-exposed infants. Non-breastfed infants receive 80 mg subcutaneous (SC) within 72 hrs of birth. Infants and mothers receive ART to prevent transmission. Infants have safety assessments and VRC07-523LS levels at 24 hrs, week 2, 4, 8, 12 and every 12 weeks through week 96. The target week 12 plasma level is 10 mcg/mL: the leve needed to neutralize 90% of tier II viruses in a multiclade panel. Plasma VRC07-523LS levels are determined through week 12 and compared to previously reported levels of VRC01. Results: The non-breastfed cohort fully accrued (N = 11) from US sites Jan-Sep, 2019. All infants received 80 mg VRC07-523LS SC within 72 hours of birth (mean 1.5 days), resulting in an average dose of 28 mg/kg (range 23 to 32 mg/kg). Enrollees were 45% male, 73% Black, 18% Hispanic. One infant withdrew after 4 weeks. VRC07-523LS was well tolerated. Local reactions were rare and mild: 1 infant had injection site erythema of 0.5 cm and 1 had tenderness. Five infants developed Grade 3/4 events within 28 days of receipt of VRC07-523LS (vomiting [N = 2], neutropenia, hyperkalemia, and parainfluenza sepsis), none considered related to study treatment. Pharmacokinetic measures through week 12 show average levels of 68.7, 31.1, 16.3mcg/mL at weeks 4, 8, and 12, respectively. Mean VRC07-523LS levels exceeded those previously reported for VRC01 20 mg/kg SC at week 2, 4, and 8. Ongoing growth contributed to the fall in VRC07-523LS concentration but levels remain over the target of 10 mcg/mL at week 12. Conclusions: We identified no safety or tolerability findings when VRC07-523LS is administered to neonates. Week 12 is an appropriate time for a second dose in infants with ongoing breastmilk exposure. VRC07-523LS, with its enhanced potency and extended half-life, could achieve target levels for the duration of breastfeeding with dosing every 3 months.