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Spent mushroom substrate (SMS) and NPK (15:15:15) fertilizer were assessed under field conditions for their comparative effects on white and orange-fleshed sweet potato varieties in Umuahia southeastern Nigeria. The experiment was a split-split plot in randomized complete block design with three replicates. The main plot treatments were two sweet potato varieties (white-fleshed TIS87/0087 and orange-fleshed Umuspo 3). The split plot treatments were five NPK fertilizer rates (0, 100, 200, 300 and 400kg/ha) while the split-split plot treatments were three SMS levels (0, 2 and 4t/ha). Averaged across sweet potato varieties and NPK fertilizer, SMS significantly increased leaf area index, shoot biomass and storage root yield. Application of NPK fertilizer increased leaf area index and shoot biomass in both years and storage root yield in 2019. The white-fleshed TIS87/0087 variety produced significantly higher shoot biomass than Umuspo 3 in both years. TIS87/0087 had higher root yield than Umuspo 3 in 2018, but in 2019, the latter out yielded the former. Three-way interactions were significant for shoot biomass in 2018 and for storage root yield in both years. The highest shoot biomass (28.70 – 30.0t/ha) in 2018 was obtained from TIS87/0087 at moderate rates of 2t/ha SMS and 300kg/ha NPK fertilizer and from Umuspo 3 at 2t/ha SMS and 200kg/ha NPK fertilizer. The highest storage root yield 30.0t/ha was obtained from TIS87/0087 at 4t/ha SMS alone in 2018 and 37.1t/ha yield from Umuspo 3 at 4t/ha SMS only in 2019. The results showed that 4t/ha SMS was sufficient to promote high root yields in sweet potato in the area.