Withdrawal, with measurement of systolic BP and pulse rate, was observed during administration of methadone mixture to heroin addicts after a drug fast of 12 to 24 h. Four subjects were regarded as nonaddicts. In the remainder, there was significant reduction of systolic BP without a titration end point. Nonaddicts and mildly and moderately addicted subjects could be differentiated after a 10-mg dose of methadone. It is hypothesized that tolerance to methadone resembles immunity comparable to that against infections, and not a dose-response curve. Factors making oral methadone less preferable to needle-using addicts include delayed gastric emptying, first passage through the liver, and possible endogenous endorphin/encephalin response. Further studies are suggested.