Immunochemical and functional properties of control and Cystic Fibrosis (CF) alpha 2-Macroglobulin (alpha 2M) are compared. Crossed immunoelectrophoresis and Ouchterlony double diffusion revealed no qualitative differences between the two alpha 2-M preparations. Trypsin-esterase activity assayed with BAPNA as a substrate, in the presence of an excess STI, gave similar ratios between total and active alpha 2M. These alpha 2M-trypsin complexes were equally stable under various experimental conditions and maintained a constant STI non-inhibited esterase activity. Normal and CF-alpha 2M-trypsin complexes were taken up by normal human fibroblasts to a similar extent during a four hour period. The only significant difference was observed when the uptake of alpha 2M from untreated sera was examined. The uptake of alpha 2M from CF sera was always lower than from pooled control sera despite large variation. Mixing of control and CF serum did not affect the normal uptake and other serum components were taken up to the normal extent. Intracellular degradation of CF alpha 2M had a half life of 2.0 to 2.8 hours, which compares well to the normal half life of 2.2 hours. More work needs to be done on the nature of the interaction between alpha 2M and proteases before a reasonable explanation for the molecular nature of the abnormal behavior can be sought.