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Procedures are described for the isolation of crystalline a-lipoic acid from acid-hydrolyzed liver residue. This isolation represents a 300,000to 600,000-fold concentration, with a 2.5% over-all recovery of activity in the form of crystalline alipoic acid. Data are presented which indicate that a-lipoic acid is the cyclic disulfide derived from 4,s-, 5,8or 6,s-dimercapto-n-caprylic acid.Previous studies have demonstrated that a variety of biological preparations contain a substance or substances which can replace acetate in its growthpromoting function for some lactic acid bacteria and are required for the oxidative decarboxylation of p y r u~a t e .~-~ The terms "acetate-replacing factor" and "pyruvate oxidation factor" were used to denote this biological activity, which has been shown to be exhibited by a group of chemically related catalytic agenk5t6 Biological activity corresponding to that possessed by these factors has been shown to be exhibited by concentrates of ( ' p r~t o g e n , "~ an essential growth factor for Tetrah y m e n a geleii.'These factors are released from materials of natural origin by the action of enzymes or by acid or base hydrolysis. Acid hydrolysis results in maximum release of activity in the form of only two of the active principles, which are acidic in na-(1) The isolation of crystalline a-lipoic acid was effected a t the University of Texas (LJR) and in the Lilly Resexrch Laboratories (GHFS) using a combination of procedures developed by the three cooperating groups and predominantly an assay procedure developed by one of the authors (ICG). Characterization and structural determination were carried out mainly by the other authors in the Lilly Research Laboratories.(2) B. M . Guirard, E. E. Snell and R .