The high nutritional value of fish makes it an ideal component of a healthy and balanced diet. Elevated levels of heavy metals in fish represent both an ecological and human health concern. Fish species are often the top consumers in aquatic ecosystems and thus metal concentrations in fish can act as an indicator of the state of the aquatic environment. Fish are known to bio-accumulate metals and are considered as one of the most indicative factors, in freshwater systems, for the estimation of trace metals pollution potential (Rashed, 2001). Histopathology can be an indicator of the effects of various anthropogenic pollutants on organisms and so could be used as a reflection of the overall health of the entire population in an ecosystem. This study aimed to assess the bioaccumulation of heavy metals in gills and muscles and their effects on histopathology of gills of Oreochromis mossambicus from the Indus River, Pakistan which receives potential pollutants from the domestic, municipal and agricultural runoffs.