Applying a methodological approach for process plant safety improvement and management in a high risk underground experimental facility is described rising as a reference case the Borexino experiment in the Gran Sasso National Laboratory, Italy. The adopted procedure involved utilization of both qualitative (HAZOP and FMEA) and quantitative techniques (FTA) in order to improve process safety in a high technology experimental setting where no previous experience on similar plants was available. In the paper, we describe a complete process characterization and detail the safety analysis phases that identify the main problem areas and suggested and adopted corrective actions.