The in vitro sensitivity of marrow CFU(E) to erythropoietin was assessed in normal, regenerating, and plethoric marrow and correlated to the cell-cycle distribution of the cells. Although all marrow samples demonstrated a approximately 75% S-phase distribution, regenerating, but not plethoric marrow, exhibited a 5- to 10-fold greater requirement for erythropoietin in vitro. It is concluded that altered responsiveness to erythropoietin may occur independently of alterations in the CFU(E) cell cycle. Secondly, alterations in erythropoietin sensitivity occur under conditions of marrow regeneration but not polycythemic suppression.