Recent studies indicate cytochrome c is released early in apoptosis without loss of integrity of the mitochondrial outer membrane in some cell types. The high conductance channel MAC (mitochondrial apoptosis-induced channel) forms in the outer membrane early in apoptosis of FL5.12 cells. Physiological (micromolar) levels of cytochrome c alter MAC activity and these effects are referred to as Type 1 and Type 2. Type 1 effects are consistent with a partitioning of cytochrome c into the pore of MAC and include a modest decrease in conductance that is dose- and voltage-dependent, reversible, and an increase in noise. Type 2 effects may correspond to plugging of the pore or destabilization of the open state. Type 2 effects are a dose-dependent, voltage-independent, and irreversible decrease in conductance. MAC is a heterogeneous channel with variable conductance. Cytochrome c affects MAC in a pore-size dependent manner with maximal effects of cytochrome c on MAC with conductance of 1.9 nS to 5.4 nS. The effects of cytochrome c, ribonuclease A, and high salt on MAC indicate that size, rather than charge, is crucial to their effects on MAC. The effects of various MW dextrans indicate the pore diameter of MAC is slightly larger than 17-kDa Dextran, which should be sufficient to allow the passage of 12-kDa cytochrome c. These findings are consistent with the notion that MAC is the pore through which cytochrome c is released from mitochondria during apoptosis.