The high cost and clinically associated side-effects of plasma exchange treatment warrant development of on-line plasma fractionation techniques. Cryoglobulin removal from cryoglobulinemic plasma is particularly amenable to membrane filtration in the cold (cryofiltration). Temperature effects on filtration were studied in vitro using a large pore (nominal average size, 3 microns), low surface area (0.14 m2) filter. Plasmas with high concentrations of cryoprecipitable proteins (CPP; greater than 1.1 micrograms/ml) and immune complexes (IC; greater than 400 U/ml) were obtained from consenting cryoglobulinemic patients by plasma exchange. Removals of IC and CPP were highly temperature dependent, and high ratios of IC, CPP, and albumin removal were achieved (e.g., sieving coefficient [SC] = 0.05 and 0.91 for CPP, and SC = 0.94 and 0.95 for albumin at 4 degrees C and 23 degrees C, respectively). Clinically required volumes of plasma (greater than 2L) were processable. Cryofiltration with this new, high performance cryoglobulin filter is selective and may substantially reduce the clinical need for plasma replacement products.