In recent years, nanotechnology has been developed dramatically. The use of nanoparticles in different industries and their release into the environment leads to stress due to their presence in the natural environment. In recent decade, it has been proposed to use different compounds in fish diets to improve performance and stress response. One of these compounds is nucleotides (NT), with low molecular weight which has several functions in fish lifecycle. The aim of this study was to evaluate the efficiency of the NT added to the diet of rainbow catfish Pangasianodon hypophthalmus in dealing with various concentrations of waterborne silver nanoparticles and silver nitrate. The fish were fed on diets containing NT (0.75%) or a control diet for 10 weeks. At the end, 40 individuals from each group of fish fed on diet contacting NT or without NT were randomly selected (mean weight 12 ± 0.26 g). Each group of fish were subjected to different concentration of silver compounds including 0 as control, 1 and 20 µg/L of silver nanoparticles, 1 and 20 µg/L and silver nitrate for 10 days under static renewal conditions. So, each group contained of 8 fish. At the end of the period, gill, liver, kidney and intestine tissues were collected to evaluate histopathological changes. The gills and muscle tissue were also collected to measure silver concentration using atomic absorption spectrometry method. Histopathological changes were detected in fish subjected to highest doses of waterborne silver nanoparticles and silver nitrate in both groups of fish fed on diets containing NT or without NT in comparison to the control group. Epithelial cell hyperplasia, inflammation, necrotic epithelial cells, eosinophilic secretions and blood accumulation are the most important histopathological changes in the gill tissues. In the liver tissue, pigmentation of complications, pyknotic nuclears, cytoplasmic vacuolization of hepatocytes and fiber cells were observed. Increased number of goblet cells, villus fusion and destruction are the most obvious intestinal changes. Increased presence of red blood cells and eosinophils, glomerular development, glomerular necrosis, tubular necrosis and inflammatory exudate were observed in the kidney. Based on organ index (I org ), the highest changes was observed in the liver tissue of fish fed on diets without NT subjected to the highest dose of silver nanoparticles. However, no significant differences was found in I org when comparing same tissue of fish fed on different diets subjected to the same treatment (p 0.05). Silver tend to accumulate more in the gill in comparison to the muscle tissues in all treatments. The concentration of silver was significantly lower in the gills of fish fed on diet containing NT in comparison of those fed without NT. In general, the results of this study showed that although dietary NT could cause some differences in the rate of silver accumulation at least in the gill tissues of rainbow catfish, no significant differences were observed in histopathological alternations. Keywords : Nanotechnology, Silver nitrate, Atomic absorption, Organ index (I org ), Accumulation