We investigated cation transport and cell volume regulation in erythrocytes of CD1 and C57/B6 mice. Swelling of cells from either strain stimulated K+ efflux that was insensitive to ouabain, bumetanide, and clotrimazole. Seventy-five percent of swelling-induced K+ efflux was Cl- dependent (inhibited by sulfamate or methanesulfonate, partially by NO3-, but not by SCN-) and was inhibited by okadaic acid (OA; 50% inhibitory concentration = 18 +/- 6 nM in CD1 and 10 +/- 4 nM in C57/B6). In both strains, K+ efflux into isotonic medium was stimulated by staurosporine or by N-ethylmaleimide, and the latter was partially blocked by pretreatment of cells with OA. When cells of either strain were incubated in hypotonic medium or preswollen isosmotically with nystatin, OA-sensitive regulatory volume decrease (RVD) and K+ loss were observed. RVD produced by hypotonic swelling was prevented by Cl- replacement with sulfamate or methanesulfonate. These properties suggest the presence in outbred and inbred mouse erythrocytes of RVD mediated by K(+)-Cl- cotransport.