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A field experiment was carried out in Adiyo, Bonke, Chencha, Sodo zuriya, and North Ari districts, they are found in Southern Ethiopia, during the 2019 main production season. The objective of the experiment was to evaluate the effectiveness of the integrations of host resistance and application of fungicides with designated spray frequency on Fusarium head blight under natural epiphytotic conditions and to determine the management effects on yield and yield components of wheat. The treatments consisted of wheat cultivars (Shorima and Hidase) and fungicides (Propiconazole and Tebuconazole) with four spray frequencies, including an unsprayed one. The experiment was arranged in a split-split plot design with three replications. Wheat cultivars were assigned to the main plots and fungicides allotted to the sub-plots, while the spray frequencies were appointed to sub-sub plots. Results exhibited that integration of wheat cultivars and fungicides with spray frequencies significantly (p < 0.001) reduced disease pressure and increased grain yields across the locations. The highest disease severity (36.46%) and area under disease progress curve (AUDPC) (404.78%-day) and lowest grain yield (2.42 t ha -1 ) were recorded at North Ari. The lowest severity (7.70%), and AUDPC (130.26%-day), and the highest grain yield (6.68 t ha -1 ) were recorded in Bonke. The lowest severity (4.78 and 5.74%) and AUDPC (52.86 and 59.78%-day) were recorded from Shorima due to integrated use of Tebuconazole with three and two times spray frequencies, respectively. The highest grain yield of 5.30 t ha -1 was recorded on Shorima in combination with Tebuconazole with three times spray frequencies. The grain yield loss of 46.49% was computed on unsprayed plots of Hidase cultivar. Overall, the results exhibited a combination of moderately resistance wheat cultivars supplemented by fungicide with appropriate spray frequencies right at disease onset reduced disease pressure and increased grain yield. Planting of Shorima combined with Tebuconazole with three times spray frequencies was found effective in reducing FHB epidemics and increasing grain yield with the highest monetary advantage. Therefore, this could be recommended to growers in the study areas and similar agro-ecologies to manage F. graminearum causing FHB in wheat., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)