Our finding that C3 deficiency led to significantly increased arthritis severity in a hematogenous S. aureus arthritis model but not in a local S. aureus arthritis model strongly suggests that the deleterious effect of C3 deficiency in hematogenous septic arthritis was due to the critical role of C3 in the early stage of the disease, i.e., before the bacteria reach the joint cavity. Here, C3 is linked to arthritic joint disease.