The oxidized disulfide form of the ubiquitous tripeptide glutathione (gamma-glu-cys-gly) (GSSG) is shown to produce transparent, thermoreversible gels in aqueous solutions of dimethyl sulfoxide, dimethylformamide, and methanol, at GSSG concentrations as low as 1.5 mM. The gels bind Congo Red and exhibit dramatic green birefringence when observed between crossed polarizers, characteristic of amyloid structures. By transmission electron microscopy, the gels appear to consist of a network of fibrous structures about 75 nm in diameter. Several structurally related peptides, including the glutathione isomer glu-cys-gly and the aspartyl analogue of glutathione (beta-asp-cys-gly), failed to produce gels under similar conditions. These results suggest that the interactions which produce gelation are highly specific and that the unusual peptide geometry introduced by gamma-glu-cys linkage is critical to the gelation behavior. (1)H NMR indicates solvent-dependent perturbation of the gamma-glutamyl alpha- and beta-protons and circular dichroism reveals a shift in the geometry of the disulfide bond under conditions producing gelation. We propose that in appropriate organic solvents, GSSG self-assembles into an extended network of beta-sheetlike structures capable of immobilizing bulk solvent. While obviously speculative, it is interesting to consider possible physiological consequences of glutathione self-recognition in such processes as abnormal protein aggregation and the thiol-disulfide exchange which is believed to participate in protein folding.