Immune checkpoint blockade of the programmed cell death protein 1 (PD-1) pathway by monoclonal antibodies (Abs) has shown promising clinical benefit in the treatment of multiple cancer types. We elucidated the contribution of the fragment crystallizable (Fc) domains of anti-PD-1 and anti-PD-ligand 1 (L1) Abs for their optimal anti-tumor activity. We revealed that distinct Fcγ receptor (FcγRs) dependency and mechanisms account for the in vivo activity of anti-PD-1 versus anti-PD-L1 Abs. Anti-PD-1 Abs were found to be FcγR independent in vivo; the presence of FcγR-binding capacity compromises their anti-tumor activity. In contrast, the anti-PD-L1 Abs show augmented anti-tumor activity when activating FcγR binding is introduced into the molecules, altering myeloid subsets within the tumor microenvironment. Display omitted •Anti-PD-1/PD-L1 Abs differ in their FcγRs requirements for optimal activity•The activities of anti-PD-1 Abs are FcγR independent•Engagement of activating FcγRs by anti-PD-L1 Abs augments the in vivo activity•Anti-PD-L1, if bound to FcγR, alters myeloid subset composition within the TME Dahan et al. report that Fcγ receptor engagement augments the anti-tumor activity of anti-PD-L1 antibodies (Abs) but compromises the anti-tumor activity of anti-PD-1 Abs. These findings provide rationale for Fc engineering of these Abs to optimize anti-tumor efficacy.