The complete amino acid sequence has been determined for a 50,000-dalton fragment that is an internal segment of the single polypeptide chain of human ceruloplasmin [ferroxidase; iron(II):oxygen oxidoreductase, EC 1.16.3.1]. The fragment (designated Cp F4) contains 405 amino acid residues, has one glucosamine-containing carbohydrate unit, and, together with the 19,000-dalton fragment that follows it, accounts for the carboxyl-terminal half of the molecule. Fragment Cp F4 has a very nonuniform distribution of certain amino acid residues, which show a high potential to be adjacent to or one residue separated from a similar amino acid. This is most pronounced for acid and amide residues (65% clustered), aromatic residues (56% clustered), and basic residues (41% clustered). In addition, there is a long-range clustering of proline residues at the amino- and carboxyl-terminal 60 residues (50% clustered). Also, there are a number of short repeated segments of sequence. Calculations based on parameters predictive of secondary structure folding patterns indicate that the 50,000-dalton fragment has a low content of alpha-helix and is predominantly beta-sheet, beta-turn, and random in structure. Limited enzymatic cleavage of human ceruloplasmin to yield 67,000-, 50,000-, and 19,000-dalton fragments occurs at specific exposed sites of random structure in between domain-like regions.