Background: To investigate relationships between infant body composition (BC) and human milk (HM) immunomodulatory proteins (IMPs) during the first 12 months of lactation. Methods: BC of breastfeeding dyads (n = 20) was measured with ultrasound skinfolds (infants) and bioimpedance spectroscopy (infants/mothers) at 2, 5, 9, and/or 12 months post partum. Breastfeeding frequency, 24-h milk intake, and IMP concentrations (lactoferrin, lysozyme, secretory immunoglobulin A (sIgA)) were measured, and calculated daily intakes (CDIs) were determined. We used linear regression/mixed-effects models and adjusted results for multiple comparisons. Results: No associations were seen between maternal characteristics and IMP concentrations/CDIs or between IMP concentrations and infant BC. Lactoferrin CDI was negatively associated with infant fat-free mass index (P = 0.002); lysozyme CDI was positively associated with infant fat mass (P = 0.004) and higher fat mass index (P = 0.004) measured with ultrasound skinfolds. Conclusion: In this small cohort of infants’ breastfeed on demand during first year of life, we report differential associations of HM IMPs with infant BC, showing that in addition to their critical role in shaping infant immunity, lactoferrin, and lysozyme also influence development of infant BC, highlighting the importance of breastfeeding for 12 months and beyond. Impact: HM IMPs (concentrations and, most importantly, daily intakes) time-dependently and differentially associate with development of infant lean mass and adiposity during first 12 months of lactation.There is no information on how intakes and concentrations of these components affect development of infant BC.HM contains IMPs—lactoferrin, lysozyme, and sIgA, which not only play a critical role in shaping infant immunity, but also influence infant growth and development of BC, highlighting the importance of breastfeeding for 12 months and beyond and warranting careful consideration of the dose effects of supplemented formula.