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Immuno-PET is a powerful tool to noninvasively characterize the in vivo biodistribution of engineered antibodies. Methods: L1 cell adhesion molecule-targeting humanized (HuE71) IgG 1 and IgG 4 antibodies bearing identical variable heavy- and light-chain sequences but different fragment crystallizable (Fc) portions were radiolabeled with 89 Zr, and the in vivo biodistribution was studied in SKOV3 ovarian cancer xenografted nude mice. Results: In addition to showing uptake in L1 cell adhesion molecule-expressing SKOV3 tumors, as does its parental counterpart HuE71 IgG 1 , the afucosylated variant having enhanced Fc-receptor affinity showed high nonspecific uptake in lymph nodes. On the other hand, aglycosylated HuE71 IgG 1 with abrogated Fc-receptor binding did not show lymphoid uptake. The use of the IgG 4 subclass showed high nonspecific uptake in the kidneys, which was prevented by mutating serine at position 228 to proline in the hinge region of the IgG 4 antibody to mitigate in vivo fragment antigen-binding arm exchange. Conclusion: Our findings highlight the influence of Fc modifications and the choice of IgG subclass on the in vivo biodistribution of antibodies and the potential outcomes thereof., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)