In an investigation of the efficacy of paroxetine in relapse prevention and prophylaxis of depression, patients who met DSM-III-R criteria for major depression with a history of two or more previous episodes in the preceding four years and who had responded to eight weeks treatment with paroxetine, were randomized double-blind to receive either paroxetine 20-30 mg or placebo for one year. One hundred and seventy-two patients entered open treatment of whom 141 completed eight weeks treatment. One hundred and thirty-five responders entered the double-blind placebo-controlled study. There was a significant advantage for paroxetine compared with placebo in the reappearance of depression (p < 0.01) and in the time to reappearance (p < 0.001) over the one-year study. A significant advantage was seen for paroxetine compared with placebo in the first four months in relapse prevention (p < 0.01) and in the time to relapse (p < 0.005), and in the later period of treatment in preventing recurrence in the time to recurrence (p < 0.05). Paroxetine was effective in preventing the reappearance of depression following an acute illness. These results confirm the benefit of long-term pharmacotherapy for treating depressive illness.