Safety is an aspect of primary relevance in early-process design and can hardly be neglected: the consequences of accidents in chemical plants have always high impact on economics and reputation. In the phase of alternative technologies’ evaluation, applying inherent safety approaches helps in identifying the major safety challenges of process schemes, orienting the final selection. In the present work, an inherent safety assessment was performed to compare two innovative fuels’ production facilities: biodiesel from microalgae and methanol synthesized via CO2 catalytic hydrogenation. The two schemes were developed to fulfil an industrial scale production, considering the best available technologies in terms of yields and energetic economy for both cases. The inherent safety performances were evaluated through a multi-criteria approach using key-performance indicators (KPIs): potential accident scenarios were simulated, followed by the identification of consequences and relative occurrence frequencies, as to quantify the risks affecting human target. The results enabled to identify the inherently safer option among two innovative processes for energy-transition fuels.