The cereal leaf beetle, Oulema melanopus L., is an economically important pest species, reducing crop yields in many cereal growing parts of the world. Available studies on yield depression in winter wheat in relation to the density of O. melanopus revealed inconsistent results, creating uncertainty about economic thresholds for pest control. We present results from a series of controlled field trials over a 4-yr period (2014–2017) in Switzerland to examine the impact of artificial defoliation (0, 20, 40, and 60% of flag leaf area removed in 1-m² field plots) on yield and yield components in winter wheat. The applied defoliation treatments correspond to field infestations levels of approximately 2–6 larvae per stem. Analysis of the combined data from 11 location-years revealed a significant linear decrease in yield per ear with increasing defoliation intensity. Yield per ear declined at a rate of 1.14% (SE = 0.28) per 10 percentage-point increase in defoliation. Similar results were found in a parallel series of field trials in which a 40% defoliation treatment was applied to eight common wheat cultivars. Interestingly, however, three cultivars showed complete tolerance in yield to defoliation. Data from two trials with natural defoliation by larvae revealed equally low levels of yield loss by feeding of O. melanopus. Based on the experimentally derived yield loss function, we calculated economic injury levels for a range of crop values. These will serve as benchmarks in the development of IPM decision-support tools for managing cereal leaf beetles in winter wheat.