Atlantic Salmon (Salmo salar L.) are sensitive to the inclusion of soybean meal in the diet which can result in inflammation in the distal intestine. Expression of S100 genes have been shown to be upregulated as part of the inflammatory response to antinutritional factors in soybean meal. These genes are also involved in calcium homeostasis in marine teleosts. We examined expression of S100I2 and S100V2 genes coding for calcium-binding proteins in the distal intestine and liver between groups of Atlantic Salmon fed a fishmeal (FM) or soybean-meal (PM) diet for 12 weeks. These two genes have been previously shown to differ in binding motifs and share variable sequence identity. Juvenile Atlantic Salmon (71.25 ± 0.76 g) were cultured in 140 L tanks using flow-through freshwater at 15 oC and randomly assigned to FM or PM diet groups in triplicate. Fish were fed daily to satiation and subsampled from each tank every four weeks. Expression of S100I2 in the distal intestine was elevated by 8 weeks but expression did not differ between diets. Expression of S100V2 was significantly elevated in the distal intestine of fish fed the PM diet compared to fish fed the FM diet. Increased expression of S100V2 but not S100I2 at 8 and 12 weeks in fish fed the PM diet differs from observations in previous studies using Rainbow Trout and implies Atlantic Salmon raised in freshwater may regulate expression of S100V2 and S100I2 in their distal intestine differently than Rainbow Trout. Expression of S100I2 and S100V2 in liver was not different between dietary treatments. Semi-quantitative histological scores confirmed mild but significant distal enteritis in the PM diet group but not in the FM diet group. Overall, these results provide further understanding in the expression of S100 genes and inflammatory processes associated with soy-induced distal enteritis in salmonids.