Human red blood cells (RBCs) when suspended in a Low Ionic Strength medium (LIS) demonstrate characteristic triphasic shape changes (morphological response, MR) and become reduced in volume. Tahitian Tabari Noni juice (Tb), after being given during the terminal phase of MR, was shown to initiate an unusual cell response. This response can be described as a volumetric four-phasic response including first a shrinking phase, attributed to the initial sucrose-induced shrinkage during typical MR, a rapid first swelling phase, induced by application of the juice, followed spontaneously by the occurrence of a more prolonged second shrinking phase, which culminated in the swelling and hemolysis of the cells. All the phases of volumetric response can be independently regulated by chloride, DIDS, cations Ca2+, Ag+, Hg2+ or plasma. The second shrinking phase is not inhibited by clotrimazole, a known inhibitor of Gardos channels, and can be replicated by a mixture of two ionophores (valinomycin and CCCP), suggesting the involvement of the putative K+/H+ exchanger as a mechanism of this phase. We suggest that the erythrocyte membrane is equipped with additional molecular systems, poorly characterized at present, that regulate the cell shape and volume. The cell should, therefore, be considered as an “active” responsive system instead of a “passive” osmometer-like structure.