Cryoglobulinemic vasculitis (CryoVas) is the most common symptom of cryoglobulinemia. However, the mechanism by which cryoglobulins (CGs) induce vascular injury remains unclear. Herein, serum samples from patients with type I, II, and III cryoglobulinemia were analyzed, with healthy individuals as controls. Dynamic light scattering and electron microscopy revealed amorphous CG aggregates, with sizes increasing progressively from type I to III. Cytotoxicity and apoptosis assays demonstrated CG aggregates alone caused no direct harm to M1 macrophages or human umbilical vein endothelial cells (HUVECs). However, CGs were endocytosed by M1 macrophages, triggering secretion of TNF-α, perforin, and IL-1β, which induced HUVEC apoptosis. Type II/III CGs exhibited stronger pro-inflammatory effects than type I, correlating with their structural aggregation tendencies. These findings challenge the notion of direct CG cytotoxicity, instead implicating macrophage-mediated cytokine release as the primary driver of vascular injury in CryoVas. The study highlights immune activation—rather than intrinsic CG toxicity—as central to pathogenesis, offering new insights for therapeutic strategies targeting macrophage-derived inflammatory pathways. This mechanistic distinction between cryoglobulin types may also inform diagnostic approaches based on structural and functional profiling of CG aggregates.