The effect of pH changes on neuromuscular (NM) transmission, both in the presence and in the absence of muscle relaxants (MR), was investigated using phrenic nervehemidiaphragm preparations of rats. The first finding of this study indicated that the primary site of action of pH changes in the absence of MR is muscle itself and not the NM junction. The second finding was that the effect of pH changes on the potency of d-Tc and vecuronium was very different from that of metocurine, pancuronium or alcuronium. The action of d-Tc and vecuronium was potentiated in acidosis and antagonized in alkalosis. In contrast, that of metocurine, pancuronium or alcuronium was antagonized in acidosis and potentiated in alkalosis. The above finding suggests that a difference exists between mono- and bisquaternary MR with regard to the response to pH changes.