Antagonizing Bcl-2 proteins by BH3 mimetics is a promising anti-cancer strategy. Yet, this has been associated with thrombocytopenia. Dysregulation of the intracellular Ca(2+) homeostasis in platelets by ABT-737 has been implicated in this phenomenon, but the underlying mechanism is a highly controversial issue. It is important to establish whether ABT-737 affects intracellular Ca(2+) homeostasis, as this may cause general adverse effects in humans. We compared ABT-737 and HA14-1, another proposed Bcl-2 antagonist with putative SERCA-inhibitory properties. We demonstrate that HA14-1, but not ABT-737, disturbs endoplasmic reticulum Ca(2+) homeostasis in platelets. HA14-1 potently inhibited ER Ca(2+)-uptake activity of SERCA2b, while ABT-737 only displayed minor inhibitory effects on ATP-driven ER Ca(2+) uptake at concentrations well above the therapeutically relevant concentrations (10 mM and higher). Moreover, HA14-1, but not ABT-737, inhibited IP(3)-induced Ca(2+) release. Our findings indicate that the effects of ABT-737 on thrombocytopenia are not due to dysregulation of intracellular Ca(2+) homeostasis.