D-Penicillamine (P-SH) added to plasma in-vitro is transformed rapidly to low molecular weight (LMW) disulfides and smaller amounts of D-penicillamine:protein conjugate. The P-SH loss through transformation is accompanied by a quantitatively similar decline in the total sulfhydryl group concentration in plasma solutions. Therefore, P-SH disappearance is predominantly through oxidation, rather than thioldisulfide interchange with plasma disulfides. The rate of P-SH transformation is dependent on the albumin concentration. It is not influenced, however, by the concentration of reduced sulfhydryl groups on plasma protein, since transformation occurs at an unattenuated rate in solutions of sulfhydryl-blocked plasma protein. D-Penicillamine:protein disulfides, therefore, are not important intermediates in P-SH oxidation in vitro. Trace amounts of transitional metals bind loosely to plasma albumin in vivo. The rate of P-SH oxidation in albumin solutions from which transitional metals have been removed is a mean of 68% of the rate in untreated solutions. Restoring [Cu2+] in treated albumin solutions to physiological levels restores the rate of P-SH oxidation. The rate of P-SH disappearance from albumin solutions correlates with [Cu2+] over a range of albumin concentrations. Catalysis of P-SH oxidation by physiological concentrations of albumin-associated Cu2+ therefore contributes to the disappearance of P-SH from plasma in vitro. A similar phenomenon may occur in vivo.