The author developed a novel screening platform to identify an enantiomeric form of the variable domain of the antibody heavy chain (d-VHH) specific for vascular endothelial growth factor A (VEGF-A). The author performed mirror-image screening of two newly constructed synthetic VHH libraries displayed on T7 phage and identified VHH sequences that effectively bound to the mirror-image VEGF-A target (d-VEGF-A). The author subsequently synthesized a d-VHH candidate that preferentially bound the native VEGF-A (l-VEGF-A) with sub-micromolar affinity. Furthermore, immunization studies in mice demonstrated that this d-VHH elicited no anti-drug antibodies (ADAs), unlike its corresponding l-VHH. These findings highlight the utility of this novel d-VHH screening platform in the development of protein therapeutics exhibiting reduced immunogenicity.