Macrophage polykaryons associated with the foreign body granuloma display several electrophysiological properties when studied with intracellular microelectrodes. One of the most evident properties is the slow hyperpolarization (2–5 s long, 10–60 mV amplitude), due to transient openings of Ca 2+-dependent K + channels, that is similar to those observed in macrophages. How this oscillation of membrane potential is triggered is not well known and the only way to repeatedly activate it under experimental control is through the intracellular injection of Ca 2+. Although this technique is important for understanding the properties of the K + channels, no information has been obtained about the way Ca 2+ levels are raised and controlled in the cytosol. Slow hyperpolarizations can also be triggered by electrical stimulation, but reproducibility is low with cells bathed in physiological solutions. We then decided to investigate the effect of depolarization on the electrophysiological properties of macrophage polykaryons exposed to bathing solutions of several ionic compositions. We show in this paper that cell membrane depolarization induced by a long current pulse can trigger several patterns of membrane potential changes and that, in the absence of extracellular Na +, repetitive oscillations of decaying amplitudes are observed in almost all the cells. They are very similar to the slow hyperpolarizations, are dependent on the presence of extracellular Ca 2+, and are blocked by quinine and D-600. Whole-cell patch clamp recording under voltage clamp conditions showed an outward current that oscillates and that also exhibits decaying amplitudes. The data presented here indicate that these oscillations are a consequence of the cyclic opening of the Ca 2+-activated K + channels and support the hypothesis that favors the participation of Ca 2+ channels and of the Ca 2+/Na + exchange system in their triggering. These two mechanisms are not enough to explain either why the K + channels close or why the membrane potential returns to the original level at the end of each cycle. The possibility of using these oscillations as a model to study the slow hyperpolarization is discussed.