A leading hypothesis of the pathogenesis of neuronal degeneration of the substantia nigra dopamine-containing cells in Parkinson's disease (PD) is excessive oxidative stress. In part, this oxidative stress is the result of the oxidation of dopamine by the action of monoamine oxidases (MAO) A and B to generate hydrogen peroxide and subsequent oxygen free radicals. Because of this hypothesis we have treated patients with early PD, not yet requiring any symptomatic treatment, with tranylcypromine, a drug that inhibits both MAO's. These patients were required to observe a tyramine-restricted diet. Thirty-seven patients on tranylcypromine have been followed by us for up to 33 months. Four patients discontinued the drug because of pending surgery. Of the remaining 33, six had adverse effects that lead to discontinuation of the drug, mainly impotency in men. Another common adverse effect encountered was insomnia, but this problem was not a cause of stopping the drug. Depression lifted in all five patients who had this problem at the time tranylcypromine was initiated. Only two patients have so far required treatment with levodopa or a dopamine agonist, and this need occurred within the first 6 months of treatment. The evaluation of all 37 patients revealed that parkinsonian symptoms improved slightly on introduction of tranylcypromine as measured by the United Parkinson's Disease Rating Scale, the Hoehn & Yahr Staging Scale, and the Schwab & England Activities of Daily Living Scale. Follow-up evaluations for a minimum of 6 months between the first post-tranylcypromine visit and the most recent visit revealed only slight worsening of parkinsonian signs and symptoms, with a mean interval of almost 1.5 years. A longer period of follow-up is needed to determine how long the severity of PD will remain mild in this group of patients.