Fusarium head blight (FHB) resistance genes, Fhb1, Fhb2, and Fhb5, which originate from Sumai 3, are among the most important that confer resistance in hexaploid wheat. Near-isogenic lines (NILs), in the CDC Alsask (susceptible; n=32) and CDC Go (moderately susceptible; n=38) backgrounds, carrying these genes in all possible combinations were developed using flanking markers and evaluated for their response to FHB and deoxynivalenol (DON) accumulation in eight environments and agronomic/end-use quality assessments from six environments. NILs were haplotyped with wheat 90K iSelect assay to elucidate the genomic composition, marker-trait associations, and epistatic interactions. Our study is the first to thoroughly investigate effects of minor alleles inherited along major FHB resistance genes in breeding programs. Other than evaluating the effects of major genes in common genetic background, the study elucidated epistatic gene interactions as they influence FHB measurements; identified loci other than Fhb1, Fhb2, Fhb5, in both recurrent and donor parents and examined annotated genes in the intervals. Genotyping revealed polymorphism on all chromosomes and that the NILs carried <3% alleles from the resistant donor. Significant improvement in field resistance (Type-I+Type-II) resulted only among CDC Alsask NILs, not the CDC Go NILs. The phenotypic response of NILs carrying combinations of Sumai 3 derived genes suggested nonadditive responses and Fhb5 was as good as Fhb1 in conferring field resistance. In addition to Fhb1, Fhb2, Fhb5, four to five resistance improving alleles in both populations were identified and three of five in CDC Go were contributed by the susceptible parent. The introgressed chromosome regions carried genes encoding disease resistance proteins, protein kinases, nucleotide-binding and leucine rich repeats’ domains. Complex epistatic gene-gene interactions among marker loci (including Fhb1, Fhb2, Fhb5) explained >20% of the phenotypic variation in FHB measurements. Among agronomic traits, introgressions resulted in lower TKW and increased plant height with Fhb5. Among end-use quality traits, SDS-sedimentation volume and grain protein content were affected. In addition to Fhb1, Fhb2, Fhb5, we identified 10 loci in CDC Alsask NILs and 9 in CDC Go NILs that affected the agronomic traits and all alleles in both populations were unique. Two of the alleles associated with linkage-drag were also associated with Type-I, II, III resistance. Immediate Sumai 3 derivatives carry a number of resistance improving minor effect alleles, other than major genes and genetic background of the recipient line and epistatic interactions can have a strong influence on expression and penetrance of any given gene. Improvements in FHB resistance can still be made by introgressing these major genes using marker-assisted selection and selecting rare segregants with improved agronomic and end-use quality.