EU FP6 funded European programme VIRTHUALIS, (2005 to 2010) aimed at the reduction of hazards in production plants and storage sites by addressing end-users’ practical safety issues, such as training of control room operators, designing of proper alarm systems, training teams to cope with emergencies, assessing of the impact of plant modifications on operators’ reliability, and helping of managers to see the impact of their decisions on sharp-end operators’ daily work; all this has been achieved through the development of an innovative technology, which has merged Human Factors (HF) knowledge and Virtual Reality (VR) technologies. The innovative character of the VIRTHUALIS technology has mainly be given by the new HF knowledge, such as the Failure Probability Estimator (FPE) tool developed mainly by the SRISL personnel, that provided solutions to cope both with identified safety-critical issues and the “driving license” to profitably exploit VR technologies. The new HF knowledge has been produced ad hoc to cope with two specific case studies, one at a STATOIL gas handling site in Norway and a second at a SONATRACH LPG handling site in Algeria. A dedicated round of exercises has been designed in each case to test human reliability and train personnel in high-risk operational activities.