Cortical spreading depression (CSD) is a depolarization wave associated with neurological disorders such as migraine, cerebral ischemia and traumatic brain injury. The mechanism of action of this phenomenon still remains unclear. Although it is suggested that extracellular K(+) accumulation contributes to CSD, other ions may play a relevant role in the mechanism of propagation of the wave. In this context, we hypothesize that Ca(2+) may play an important function in the wave propagation. Our results demonstrate that enhancing Ca(2+) influx into the cells by topical cortical application of the ionophore A23187 (10 μM, 50 μM and 100 μM solutions) increases the velocity of CSD propagation in a dose-dependent manner, and a much higher dose of this compound (2 mM) triggers CSD. In conclusion, increased Ca(2+) influx can be a key element in the induction mechanism of the CSD, and should be assessed in further experimental strategies targeting brain disorders related to CSD.