Low temperature plasma (LTP) has been proposed as a novel therapeutic method for its anti-cancer potential. However, its biological effects in combination with other physical modalities remain to be elusive. Therefore, this study was aimed to determine the effects of low temperature helium plasma (He-LTP) in combination with mild hyperthermia (HT, 42℃ for 20 min). Human lymphoma U937 cells were exposed to HT, immediately after He-LTP treatment. He-LTP in combination with HT showed enhanced cell death, which was accompanied by increased intracellular reactive oxygen species (ROS) production. These findings suggest that He-LTP can enhance the apoptotic effects of mild HT due to the increased in intracellular ROS generation as He-LTP has been known to caused marked induction of ROS in the aqueous medium. These findings would be helpful when establishing a therapeutic strategy for LTP in combination with mild HT. Here, the biological effects of LTP, and the combination with hyperthermia and LTP or LTP -activated solutions for cancer therapy have been summarized in this review.