Fusarium head blight (FHB) is one of the most difficult small-grain diseases to manage, due to the partial effectiveness of management techniques and the narrow window of time in which to apply fungicides profitably. The most effective management approach is to integrate cultivar resistance with FHB-specific fungicide applications; yet, when forecasted risk is intermediate, it is often unclear whether such an application will be profitable. To model the profitability of FHB management under varying conditions, we conducted a 2-year split-plot field experiment having as main plots high-yielding soft red winter wheat cultivars, four moderately resistant (MR) and three susceptible (S) to FHB. Subplots were sprayed at flowering with Prosaro or Caramba, or left untreated. The experiment was planted in seven North Carolina environments (location-year combinations); three were irrigated to promote FHB development and four were not irrigated. Response variables were yield, test weight, disease incidence, disease severity, deoxynivalenol (DON), Fusarium-damaged kernels, and percent infected kernels. Partial profits were compared in two ways: first, across low-, medium-, or high-DON environments; and second, across environment-cultivar combinations divided by risk forecast into "do spray" and "do not spray" categories. After surveying DON and test weight dockage among 21 North Carolina wheat purchasers, three typical market scenarios were used for modeling profitability: feed-wheat, flexible (feed or flour), and the flour market. A major finding was that, on average, MR cultivars were at least as profitable as S cultivars, regardless of epidemic severity or market. Fungicides were profitable in the feed-grain and flexible markets when DON was high, with MR cultivars in the flexible or flour markets when DON was intermediate, and on S cultivars aimed at the flexible market. The flour market was only profitable when FHB was present if DON levels were intermediate and cultivar resistance was combined with a fungicide. It proved impossible to use the risk forecast to predict profitability of fungicide application. Overall, the results indicated that cultivar resistance to FHB was important for profitability, an FHB-targeted fungicide expanded market options when risk was moderate or high, and the efficacy of fungicide decision-making is reduced by factors that limit the accuracy of risk forecasts.