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Interactions between humans and wildlife resulting in negative impacts are among the most pressing conservation challenges globally. In regions of smallholder livestock and crop production, interactions with wildlife can compromise human well-being and motivate negative sentiment and retaliation toward wildlife, undermining conservation goals. Although impacts may be unavoidable when human and wildlife land use overlap, scant large-scale human data exist quantifying the direct costs of wildlife to livelihoods. In a landscape of global importance for wildlife conservation in southern Africa, we quantified costs for people living with wildlife through a fundamental measure of human well-being, food security, and we tested whether existing livelihood strategies buffer certain households against crop depredation by wildlife, predominantly elephants. To do this, we estimated Bayesian multilevel statistical models based on multicounty household data (n = 711) and interpreted model results in the context of spatial data from participatory land-use mapping. Reported crop depredation by wildlife was widespread. Over half of the sample households were affected and household food security was reduced significantly (odds ratio 0.37 [0.22, 0.63]). The most food insecure households relied on gathered food sources and welfare programs. In the event of crop depredation by wildlife, these 2 livelihood sources buffered or reduced harmful effects of depredation. The presence of buffering strategies suggests a targeted compensation strategy could benefit the region's most vulnerable people. Such strategies should be combined with dynamic and spatially explicit land-use planning that may reduce the frequency of negative human-wildlife impacts. Quantifying and mitigating the human costs from wildlife are necessary steps in working toward human-wildlife coexistence., (© 2020 Society for Conservation Biology.)