A 2-year prophylactic trial was carried out in 31 bipolar manic-depressive subjects, comparing 300 mg/day methylene blue on a double-blind crossover basis with 15 mg/day. All patients were also maintained on lithium. Seventeen patients completed the 2-year trial. During the year the patients were treated with methylene blue at 300 mg/day, they were significantly less depressed than during the year on 15 mg/day. No significant difference in the severity of manic symptoms was shown. The trial had obvious limitations, e.g., a small number of subjects, a relatively large number of dropouts, relatively simple rating scales, doubts about blindness, and uncertainty as to whether or not 15 mg methylene blue per day could be considered a placebo. However, the results suggest that methylene blue may be a useful addition to lithium in the long-term treatment of manic-depressive psychosis and warrants further investigation.