Therapeutic administration of immunoglobulins (Ig) has the potential to precipitate thrombotic events. This phenomenon may be explained by red blood cell (RBC) aggregation, which can be potentiated by Ig. The contribution of plasma albumin and fibrinogen to Ig-induced RBC aggregation is unclear. We examined RBC aggregation in three settings: (1) patients receiving therapeutic infusions of Ig; (2) plasma supplemented in vitro with Ig; and (3) RBC suspensions in standard buffer with varying concentrations of albumin, Ig and fibrinogen. Ig infusion augmented aggregation of RBCs from patients with normal or high plasma levels of albumin, but decreased aggregation in those with lower plasma albumin concentrations. In vitro, RBC aggregation was significantly increased only when all three components, fibrinogen, albumin and Ig, were present at or above normal concentrations in the suspension, but was unaffected when any one of the components was absent from the suspension. Our results suggest a three-way interaction among fibrinogen, Ig and albumin, which synergistically induce RBC aggregation in plasma. Understanding these interactions may help predict clinically important phenomena related to RBC aggregation, such as thrombotic complications of Ig infusion.