Genetic selection has been shown to be an effective strategy to increase specific-pathogen resistance in cultured populations of fish and multiple lines of rainbow trout have been selected for resistance to particular pathogens. Interestingly, in disease challenges conducted by our group, our strain selected for growth performance and resistance to intestinal enteritis caused by high plant-protein diets (PSel) has shown evidence of elevated non-specific pathogen resistance. Here, we used multi-tissue RNAseq to compare the acute transcriptional response to experimental infection of Flavobacterium columnaris (Fc) in three lines of rainbow trout with disparate selection backgrounds (Commercial Selection w/ Fp resistance; PSel: Plant-based diet Selection; VSel: Viral-resistance [IHN] Selection). At 0, 4, 12, 24, and 48 hours post-challenge, six fish from each strain were sacrificed and kidney, liver, intestine, and spleen samples were collected for RNAseq. Illumina sequencing of mRNA-selected libraries yielded 8.6 ± 1.4 M filtered reads per sample. Differential gene expression and gene ontology annotations were conducted within each tissue to detect differences in acute responses to Fc infection. Among the selected lines, the CSel strain, which is under selection pressure for Flavobacterium resistance, showed the highest surivial rates throughout the 21-day disease challenge (Fig. 1) and also exhibited the most drastic change in gene expression profiles immediately (≤ 24 h) following Fc challenge (Fig. 2), including the most diverse upregulation of immune genes. Further genetic and temporal differences in transcriptional responses to Fc will be discussed. Results provide insights on molecular mechansims behind varying levels of genetic resistance to specific pathogens, in lines under different selective pressures.