Flows from the Grande Ronde Basalt of the Columbia River Basalt Group include several with the chemical composition of ferro-andesites. These flows have SiO2 > 55%, MgO < 4%, and also have higher Fe/Mg than the average value for Grande Ronde Basalt. They are also distinctly richer in Cs, Rb, K, Ba, La, Ce, Th, and U than the remainder of the Grande Ronde Basalt flows, and possess small negative Eu anomalies. Their Pb isotopic compositions define a mixing line with a negative slope on a 206Pb/204Pb versus 207Pb/204Pb plot. Their Nd isotopic compositions lie between 143Nd/144Nd = 0.51252 and 0.51264, and their Sr isotopic compositions lie between 87Sr/86Sr = 0.7055 and 0.7060. These values define the enriched end of the Columbia River Basalt Group spectrum on a Sr–Nd epsilon diagram (excluding the Saddle Mountains Basalt). These ferro-andesite flows also form a compositional end member of the Columbia River Basalt Group and are sufficiently distinctive to warrant special consideration. We compare them with lavas from other tholeiitic provinces. Petrogenetically, they can be related to the Grande Ronde Basalt low-Mg basalts by plagioclase fractionation, or by clinopyroxene fractionation in partially melted eclogites. However, the situation may not be that simple, as their unique isotopic compositions are closely related to those of parental mantle materials, perhaps thus requiring separate reservoirs and (or) sources. Extending this argument to other parts of the Columbia River Basalt Group suggests that the origin of these basalts may be in a system of comparatively small magma chambers in the uppermost mantle, frequently replenished from a variety of sources.