Lake Manzala is one of the economic lakes and one of the most important Delta wetlands in Egypt, due to its high productivity. The southern region of the Lake receives agriculture, industrial and sewage wastewaters without treatment from several drains; the most polluted one is Bahr El-Baqur drain. In the present study the distribution and accumulation of some heavy metals (Al, As, Cr, Co, Ni and Se) were studied in the water and the Nile Tilapia O. niloticus, during the period from winter 2012 to autumn 2013. Results showed that the concentrations of heavy metals in water followed the order Al>Ni>Cr. Heavy metals As, Co and Se were not detected in all water samples at the six selected sites. Al and Ni levels in water were higher than the international permissible limits of Australia and New Zealand. The levels of the heavy metals in gills and muscles of the Nile Tilapia followed the order Al>Ni>Co>As>Se and Cr. The concentrations of heavy metals exceeded the maximum permissible limits in all fish muscles. So, it can be conclude that the southern area of Lake Manzala is contaminated by high levels of heavy metals and the consumption of its fish is not safe and could cause health hazard to the local population as their diet depends mainly on fish.