Tissue culture has the potential of improving the livelihoods of subsistence farmers that largely rely on vegetatively propagated crops. This study assesses the impact of growing tissue-cultured sweet potatoes on yields and economic profitability among smallholder farmers in the Hwedza District of Zimbabwe. A sample of 133 smallholder farmers was chosen using a multi-stage sampling process. Primary data was collected using structured and semi-structured interviews, focus group discussions, and direct-yield measurements. The results of the study showed that yields were 0.5 and 1.8 tons per hectare for households using unimproved and tissue-cultured sweet potatoes, respectively. The net economic return for tissue-cultured sweet potatoes was Z$3,605,000 (US$36.05) per hectare while a net loss of Z$9,157,500 (US$91.58) per hectare was observed for unimproved sweet potatoes. Farmers were also constrained by an inadequate supply of improved planting material. These findings suggest the need to increase the supply of tissue-cultured planting materials and to consolidate farmer knowledge on vegetative propagation in local community tissue culture laboratories. This will enhance the role of tissue culturing sweet potatoes in the attainment of household food security.