Background and Purpose: Urinary oxalate excretion influences the development of calcium oxalate kidney stones. Urinary oxalate is derived from dietary sources and endogenous synthesis. Oxalate decarboxylase metabolizes oxalate and, if consumed, could theoretically accomplish this in the gastrointestinal tract. This study aimed to determine whether a commercially produced form of oxalate decarboxylase (Oxazyme®) could degrade oxalate in simulated gastric and intestinal environments. Materials and Methods: One buffer (pH 3.6) simulated the gastric environment, while another (pH 6.5), approximated the proximal intestine. Potassium oxalate (soluble form of oxalate) and whole and homogenized spinach (a high oxalate containing food) were incubated in the different buffered solutions, with or without Oxazyme. Oxalate content, after incubation, was measured using established ion chromatographic techniques. Results: Oxazyme resulted in complete degradation of oxalate derived from potassium oxalate in the intestinal buffer; meanwhile, oxalate derived from potassium oxalate in the gastric buffer was profoundly digested by Oxazyme. Adding Oxazyme also substantially reduced the oxalate content of both whole and homogenized spinach preparations, in either buffer. Conclusions: These in vitro findings demonstrate that Oxazyme can metabolize oxalate in both simulated gastric and small intestinal environments. © Copyright 2013, Mary Ann Liebert, Inc. 2013.