1. The effects of the cardioactive peptide FMRFamide were tested on enzymatically dissociated muscle cells isolated from hearts of the leech. These cells were normally quiescent, with resting potentials near -60 mV. 2. Superfusion of FMRFamide induced a strong depolarization in isolated heart cells (e.g., >40 mV with 10v6 M FMRFamide). The depolarization was maintained in the continued presence of peptide and persisted long after its removal. Less frequently, FMRFamide superfusion elicited an episodic polarization rhythm. 3. The response of isolated heart cells to bath-applied FMRFamide showed a Ito 2-min latency. The latency decreased with repeated applications of FMRFamide. 4. The FMRFamide response was diminished by Na+ replacement but persisted with Ca2+ channel blockade. 5. In voltage-clamped heart cells (-60 mV), superfusion of FMRFamide elicited a slow inward current with a transient and a sustained component. 6. Current-voltage (IV) curves during FMRFamide superfusion in normal leech saline showed that FMRFamide also enhanced voltage-dependent outward currents activated at depolarized levels. 7. Under conditions in which K+ currents were substantially blocked, the FMRFamide-dependent I-V curve was net inward from -90 to +50 mV. A voltage-dependent component was blocked by Co2+ and a linear component by Na+ replacement. 8. We conclude that FMRFamide elicits a persistent inward current with a Na+ component and in addition modulates both voltage-dependent Ca2+ and K+ currents that may contribute to the normal myogenic activity of leech heart muscle cells.