The in vivo metabolism of malondialdehyde (MDA) by male and female Swiss mice was investigated. Distribution of an i.p. dose of MDA is rapid and uniform throughout the body. Conversion of 14C-labeled MDA to CO2 is complete 4 hours after an i.p. dose of 5 mumol to 200 mumol with no signs of short term toxicity. The yields of CO2 from [1-14C]-beta-alanine, [3-14C]-beta-alanine, [1-14C]-sodium acetate, and [2-14C]-sodium acetate were also determined. Comparison of the yields of CO2 from this series of compounds suggests the intermediacy of malonic semialdehyde in the metabolism of MDA. High doses (600 mumol) of beta-alanine or acetate given prior to 14C-MDA reduced the yield of 14CO2. Ethanol and disulfiram were both inhibitors of MDA metabolism, indicating the involvement of aldehyde dehydrogenase in the oxidation of MDA. These data demonstrate the ability of animal tissues to rapidly remove exogenously administered MDA. They also have implications with respect to the possible pathological consequences of in vivo MDA generation.