Fc-gamma receptor (FcγR) activation by soluble IgG immune complexes (sICs) is thought to be a major mechanism of inflammation in certain autoimmune diseases such as systemic lupus erythematosus (SLE). A robust and scalable test system allowing for the detection and quantification of sIC bioactivity is missing . Therefore, we developed a comprehensive reporter cell panel capable of measuring the sIC-mediated activation of individual human and mouse FcγRs . We show that compared to human FcγRs IIB and III, human FcγRs I and IIA lack sensitivity to sICs . Further, the assay proved to be sensitive to sIC stoichiometry and size enabling us to demonstrate for the first time a complete translation of the Heidelberger-Kendall precipitation curve to FcγR responsiveness . This was validated using primary immune cells . The approach was applied to quantify sIC-mediated FcγR activation using sera from SLE patients or from mouse models of lupus and arthritis . Thus, in clinical practice, it might be employed as a test matrix toolbox enabling the evaluation of FcγR activation by sICs as a biomarker for disease activity in immune-complex mediated diseases . One Sentence Summary This study reveals selective activation of individual Fc-gamma receptors by soluble but not immobilized immune complexes, establishing a novel biomarker for autoimmune disease in humans and mouse models.