Dermo is an important disease of the eastern oyster Crassostrea virginica caused by the protist Perkinsus marinus that heavily impacts wild and cultured populations. Selective breeding has improved dermo resistance although progress has been slow, likely because dermo resistance is determined by many genes of small effects. Genomic selection (GS) is a powerful approach to genetic improvement especially for polygenic traits that are difficult to measure. GS was conducted to improve dermo resistance in a wild population from Florida over two generations. In the first generation, GS led to 10.2% increase in dermo resistance as previously reported. For the second generation, F1 oysters were again challenged with P. marinus, separated into dead (susceptible) and live (resistant) phenotypes, and used as the training population, with unchallenged oysters from the same F1 population used as the breeding population. Oysters were genotyped with a 66K SNP (single-nucleotide polymorphism) array. A genome-wide association study identified no major quantitative trait loci for dermo resistance, confirming the trait is polygenic with a heritability of 0.26. Five models were evaluated for genomic predictions and the model with the highest prediction accuracy, as determined by cross-validation in the training population, was used to calculated genomic estimated breeding values (GEBVs) for oysters in the breeding population. Oysters with the highest (~10%) or average GEBVs were selected to produce the genomic selected (FLGS) and genomic control (FLC) groups, respectively. Survivors from dermo challenge and unchallenged wild oysters were selected to produce phenotypic selected (FLP) and wild (FLWC) unselected controls, respectively. Progeny from the four groups were challenged with dermo in the lab to assess their resistance. At the end the 18-week challenge, cumulative survival was 69% in FLGS, 51% in FLP, 43% in FLC and 22% in FLWC (Figure). Compared with the genomic control FLC, the genomic selected FLGS showed 60.5% improvement in survival, while improvement in FLP (18.6%) was not significant. FLGS showed 214% increase in survival over the unselected wild control FLWC. Considering improvements made in both F1 and F2, two generations of genomic selection led to 76.9% compounded increase in survival. These results indicate that GS is effective in improving dermo resistance, and significant improvement can be achieved in two generations.