Hazards are intrinsic to a material or its conditions of storage or use [Hendershot, D. C. Inherently safer chemical process design. J. Loss Prey. Process Ind. 1997, 10 (3), 151-157]. Inherently safer designs aim to avoid hazards by design, rather than by add-on measures. The importance of inherent safety has been increasingly stressed in chemical process industries in recent years. It is the most suitable safety approach, particularly in the process design stage. This paper describes a new comprehensive inherent safety index (CISI) for use in the early process design stage. The CISI assigns equipment safety scores to individual units. in the process based on chemical, process, and connectivity scores. The chemical score considers the weighted severity score of each chemical in the unit as well as the reactivity score. The reactivity score is calculated separately for the mixture of chemicals in each unit. Since hazards can be compounded by the existence of highly interconnected units, the concept of the connectivity score is introduced. Case studies involving biodiesel and methyl methacrylate processes are used to demonstrate the new safety assessment methodology. The results of the assessment are used to compare the processes based on inherent safety, and they can potentially serve as a valuable aid to clearly identify key areas for improvement in a root-cause analysis.