Innate pattern recognition receptors such as C1q, are vital for clearance of foreign and altered-self targets. C1q has a dual role in vivo: activating the inflammatory complement pathway via C1 complex formation (C1qC1r2C1s2) and direct target opsonization, which is anti-inflammatory. Here we test the hypothesis that macrophages encountering foreign targets will increase levels of all C1 subunits while macrophages encountering damaged-self targets will not. Human monocyte-derived macrophages (HMDM) were polarized or exposed to foreign or damaged-self targets. Expression of C1 subunits by M1 inflammatory macrophages generally support the hypothesis, demonstrating increased production of C1r, C1s and C1 activity. Conversely, HMDM ingestion of apoptotic cells increased expression of C1q but not C1r or C1s. Levels of complement proteins C3, and C4 were also modulated in response to different targets. These findings suggest that macrophages are fine-tuning their response according to targets they interact with, in order to modulate the local inflammatory environment. Further characterization of these changes and understanding the molecular pathways involved may provide avenues for novel therapeutic pathways.