A mouse model with soft tissue tumour was established to assess the involvement of tumour necrosis factora (TNFa) in cancer pain and hyperalgesia. Behavioural and electrophysiological investigations were performed on C57BL6 mice which received subcutaneous injection of 700000 carcinoma cells to the plantar and dorsal side of the hind paw. Ten days post tumour cell inoculation paw withdrawal latency in response to heat stimuli had decreased from 7 s before to 3 s. In an in vitro skin-nerve preparation the majority (70%) of the heat-activated C-fibres from tumour mice had lower activation thresholds(<35°C) and exhibited higher rates of discharge during a heat stimulus compared to heat-sensitive fibres from control mice (4.2 vs 2.5 AP/s). Systemic administration of etanercept (a TNFa antagonist) prevented the development of heat hyperalgesia in tumour mice, and intraplantar injection of TNFa (10ng) evoked heat hyperalgesia within 30 minutes post injection in control mice. In addition, TNFa application induced an increase in the rate of discharge of heat-sensitive fibres in vitro. Similar TNFa effects were obtained from sensory neurones in culture. Together, our data suggest that TNFa plays an important role in the development of cancer-induced heat hyperalgesia. Supported by Sander-Stiftung and FWF