The ability of tripelennamine and chlorpheniramine to potentiate morphine- and pentazocine-induced antinociception in drug-naive and morphine-tolerant mice was tested utilizing the hot-plate method. Both tripelennamine and chlorpheniramine alone produced dose-dependent increases in hot plate latency which were naloxone reversible. Cross-tolerance developed between tripelennamine and morphine, whereas no cross-tolerance developed between chlorpheniramine and morphine. Neither tripelennamine nor chlorpheniramine significantly potentiated morphine-induced antinociception in drug-naive mice. The effects of tripelennamine and morphine were additive. Tripelennamine but not chlorpheniramine, however, significantly potentiated antinociception produced by low but not high doses of pentazocine in drug-naive mice. Furthermore, in morphine-tolerant mice, tripelennamine, but not chlorpheniramine, potentiated both morphine- and pentazocine-induced antinociception. It is concluded that the abuse of various narcotic-tripelennamine combinations can be attributed, at least in part, to a specific property of tripelennamine to potentiate narcotic effects in the drug-naive and morphine-tolerant state.