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There have been changes in catches and biological characteristics of the Nile Tilapia, Oreochromis niloticus (Linnaeus) in Lake Wamala (Uganda) since its introduction and establishment, but the factors which have contributed to these changes are not adequately understood. This study examined changes in catches and biological characteristics of Nile tilapia in relation to changes in temperature, rainfall and lake depth to provide an understanding of the role of changing climatic conditions. There was an increase in minimum, maximum and average temperature since 1980, but only minimum (0.021ºCyr-1) and average (0.018ºCyr-1) showed a significant trend (p < 0.05). Rainfall increased by 8.25 mmyr-1 since 1950 and accounted for 79.5% of the water input into the lake while evaporation accounted for 86.2% of the water loss from the lake. The lake depth was above 4 m during the years rainfall was above normal average of 1180 mm, except during the period 2011-2014. The contribution of Nile tilapia to total catch and CPUE changed with rainfall and lake depth up to 2000, after which they decreased despite increase in rainfall. There was a strong positive correlation between lake depth and average total length of Nile tilapia (r = 0.991, p < 0.001) and length at 50% maturity (r = 0.726, p < 0.001). The length-weight allometry between high and low lake depths was significantly different [t (6) = 3.225, p < 0.05], with Nile tilapia being heavier (for a given length) at high lake depth than at low lake depth. Fecundity of Nile tilapia was higher and egg diameter lower than what is reported in literature. Nile tilapia shifted from algal dominated diet during the wet season to include more insects during the dry season. The study showed that the catches and biological characteristics of Nile tilapia change with climate and hydrological factors and these need to be considered in management of the fisheries of Lake Wamala.