Abstract Complement independent functions of C1q include C1q’s collagen-like region (CLR) engaging the immunoreceptor LAIR-1 to restrict monocyte-derived dendritic cell (mono-DC) differentiation/activation. If C1q’s globular region (gC1q) directly engages distinct inhibitory immunoreceptors is unknown. CD33, a C-type lectin, is highly expressed on monocytes. Like LAIR-1, triggering through CD33 inhibitory motifs (ITIM) restricts monocyte/DC activity. CD33 has C2-like domains potentially recognized by gC1q; thus we hypothesized that C1q would engage CD33. We tested whole (w) C1q/gC1q/C1qCLR for binding to CD33 isoforms (CD33M: one V & one C2 domain and CD33m: C2 domain only). Analyses with purified proteins revealed that wC1q binds to both isoforms and that gC1q, but not C1qCLR, binds to CD33 C2 domains. CD33M and CD33m transfected HEK293T cells bound C1q. On THP-1 cells, masking of CD33 C2 domains by sialic acid impeded binding of C1q. Domain oriented inhibitory partnering was substantiated by coincident triggering of CD33/LAIR-1 ITIM phosphorylation in monocytes by C1q and phosphorylation of LAIR-1 but not CD33 ITIM by C1qCLR. C1q also prompted CD33-LAIR-1 crosslinking on monocytes in proximity ligation assays. Thus, CD33 is a receptor for C1q; CD33 C2 domains are biologically relevant; C1q/CD33/LAIR-1 partnering occurs in monocytes. Masking of CD33 C2 domains by sialic acid suggests a mechanism for controlling C1q-CD33 inhibitory activity.