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Background and aims Higher plants represent an optimal tool to regenerate resources while producing food in Space. However, the configuration of fertile cultivation substrates based on extraterrestrial resources is still a challenge. We evaluated the adaptability of potato (Solanum tuberosum L., cv. ‘Colomba’) to the growth on six substrates: the MMS-1 Mars regolith simulant, alone (R100) and in mixture with 30% in vol. of green compost (R70C30), a fluvial sand, alone or mixed with 30% of compost (S100 and S70C30), a red soil from Sicily (RS), and a volcanic soil from Campania (VS). Methods We assessed the physicochemical properties of the substrates, and the physiological and biometric parameters of potato plants grown in pot on these substrates, in cold glasshouse. Results Both R100 and S100 were alkaline (pH ≥ 8.6) and coarse-textured, lacking organic matter and pivotal macronutrients. The amendment with compost significantly lowered their alkaline pH and improved the chemical fertility. The sandy-loam textured VS was sub-alkaline, slightly calcareous, with higher organic C and nutrient availability than RS. This latter was neutral-to-sub-alkaline, clay textured, poorly calcareous, with significantly higher CEC than VS. Leaf CO2 assimilation rate was higher in plants grown in terrestrial soils and S100. Plant growth was greater in VS, R70C30 and S70C30, while it was reduced on R100. Plants produced healthy tubers on all the substrates. Conclusion MMS-1 regolith simulant was found poor in nutrients and unsuitable to sustain adequately the plant growth. Amendment with organic compost improved MMS-1 physiochemical properties and fertility and plant performance.