1. Free-swimming fish (Tilapia leucosticta and Rutilus rutilus) were used to determine threshold concentrations required for general anesthesia with metacaine (MS-222). The criterion for anesthesia was reached at a concentration of 1:1500 (w/w) with both fish, although the symptoms were somewhat more pronounced in Rutilus. 2. Recordings of efferent spontaneous activity in the lateral-line nerve were used as a measure of the central effect of metacaine during administration in the respiratory stream, as compared with respiration of fresh water. The reduction of activity at the end of a 3-min exposure to the drug was 70%. 3. Maximum recovery (90% of the initial activity) was reached after 30 min application of fresh water. 4. The various efferent impulse types were differentially affected by the anesthetic. 5. Direct recordings from sound-sensitive neurons in the medulla confirm the strong central effect of metacaine. 6. Irrigation of the lateral-line system with anesthetic solution also produced a reduction in afferent spontaneous activity; there was a distinct peripheral effect even at the threshold concentration. 7. Reactions of trigeminal nerve fibers to mechanical stimulation of the skin were reduced after application of a metacaine solution to the skin. This finding confirms the local anesthetic effect of the drug. 8. The anesthetic solution at a given concentration had a greater effect on the CNS than on the peripheral receptors. 9. The implications of the results with respect to the risk of misjudging the depth of general anesthesia are discussed. 10. Because of the complexity of its anesthetic efficacy, it is recommended that metacaine not be used for neurophysiological investigations, but rather that the animals be immobilized by means of muscle relaxants.