The influence of external Na+ and Ca2+ on the efflux of Ca2+ from highly purified sarcolemmal vesicles isolated from dog ventricles is examined. Na+-Ca2+ exchange is used to initially load the vesicles with Ca2+. Ca2+-induced Ca2+ efflux is activated if a monovalent cation is also present in the efflux medium. The order of potency of monovalent cations in stimulating Ca2+-induced CA2+ efflux is K+ approximately Li+ greater than choline+. Ca2+-induced CA2+ efflux is half-maximal at [Ca2+] = 10 microM and [K+] = 10 mM. Na+ can activate Ca2+-induced Ca2+ efflux, but this is difficult to quantitate as Na+ also induces CA2+ efflux by itself. Na+-induced CA2+ efflux (in the absence of Ca02+) is half-maximal at [Na+] = 12.5 mM. The curve describing the dependence of Ca2+ efflux on [Na+] is sigmoid suggesting the participation of at least 2 Na+ in this process. Unlike Ca2+-induced CA2+ efflux, Na+-induced Ca2+ efflux is independent of the presence of other monovalent cations. The maximal Na+- and CA2+-induced CA2+ effluxes are comparable. Na+ and Ca2+ appear to compete for binding sites which result in induced Ca2+ efflux. The relevance of these findings to Ca2+ efflux studies in intact cardiac tissue is discussed.