Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting adverse effect of neurotoxic chemotherapeutic agents. Recent studies have suggested clinical utility of limb hypothermia in reducing CIPN. However, conventional cooling methods such as ice packs are unable to provide thermoregulated cooling and cause frostbites. Cooling modalities offering thermoregulation have been developed for sports injury and orthopaedic indications, but not explored for preventing CIPN. This study aims to determine the safety, tolerability and optimal parameters of three cooling modalities for delivery of limb hypothermia in healthy subjects, prior to testing in cancer patients for prevention of CIPN. Healthy subjects underwent limb hypothermia by either: continuous-flow cooling, cryocompression or frozen gloves. Skin temperatures and tolerance scores were monitored. Overall, 58 subjects underwent limb hypothermia. No adverse events were observed barring transient erythema. Both continuous-flow cooling and cryocompression are feasible, safe and tolerable methods for delivery of limb hypothermia. Cryocompression achieved lower skin temperatures than continuous-flow cooling with similar safety profiles. Frozen gloves were minimally tolerated. Cryocompression may provide greater efficacy in preventing CIPN, with clinical trials currently underway.