The complement protein C1q and its receptors, gC1qR and cC1qR, are expressed on various normal as well as malignant cells and can play both pro- and anti-proliferative roles. These opposing roles, in turn, depend on the localization of these molecules i.e. surface versus secreted. The present studies were designed to examine the functions of the soluble (secreted) and membrane forms of both C1qRs and C1q using the SkBr3 Her2+ cancer cell line as a model for breast cancer. Our results show that SkBr3 cells express not only gC1qR and cC1qR, but also C1q. Importantly, co-culture of SkBr3 cells with either purified C1q or the C1q globular head (gh) modules, ghA, ghB and ghC, resulted in a significant inhibition of cell growth with ghA and ghC showing stronger effects than ghB. Conversely, co-culture of SkBr3 cells with either anti-C1q or an antibody recognizing the gC1qR site on ghA, resulted in complete inhibition of cell growth indicating that like gC1qR, membrane-bound C1q is also pro-proliferative. Co-culture of SkbR3 with anti-cC1qR was also found to inhibit cell proliferation. In contrast, addition of purified recombinant gC1qR to SkBr3 cells enhanced cell growth and reduced cell death even under nutrient-depleted conditions suggesting that it is a pro-proliferative autocrine signal. Although SkBr3 cells do not secrete C1q during normal cell proliferation, they release gC1qR. Interestingly, the anti-proliferative effect of exogenously added C1q was inhibited when added to SkBr3 cells in gC1qR-rich medium lending credence to the postulate that secreted gC1qR not only provides an autocrine signal for proliferation but also serves as a molecular checkpoint in the tumor cell microenvironment by denying C1q access to the cell surface. These observations demonstrate that cell surface-expressed C1q and C1qRs are involved in breast cancer cell proliferation, and that soluble gC1qR appears to serve as an autocrine growth signal. Thus, the C1q receptor–C1q axis may provide potential novel targets for therapeutic intervention in breast cancer.