Abstract: In the present study, we have focused on the specific question of whether ultrasound application (ULS) delivered with optimized parameters for cavitation generation can stimulate apoptosis in lymphoid cell lines. Suspended T and B lymphoid cell lines (Jurkat and Raji, respectively) were exposed to low frequency ULS (750 KHz) at an intensity level of 54.6 W/cm2 spatial peak temporal average (SPTA) at focal area, which was found to be the optimal physical parameter to induce apoptosis in these malignant cell lines. Unsonicated cells and cells exposed to γ-radiation (20 Gy) using 137Cs source were used as control. Apoptosis was evaluated by cell morphology changes, cell-cycle analysis, and phosphatidylserine exposure. Fraction of cells with low mitochondria membrane potential was observed 1 h after sonication, accompanied by cytochrome c release from mitochondria to the cytosol and caspase-3 activation. Here we present evidence that ULS exposure with cavitation formation on malignant lymphoid cell lines differs from γ-radiation and is associated with time-dependent apoptosis, which is mitochondria-caspase dependent.