An integrated biosphere model (IBIS) and a hydrological routing algorithm (HYDRA) are used in conjunction with long time-series climate data to investigate the response of the Lake Chad drainage basin of northern Africa to climate variability and water use practices over the last 43 years. The simulated discharge, lake level, and lake area of the drainage basin for the period 1953–1979 are in good agreement with the observations. For example, the correlation coefficient (r2) between the simulated and the observed level of Lake Chad for the 288 months of available observations is 0.93. Although irrigation is only a modest portion of the hydrology in the period 1953–1979; representing only 5 of the 30% decrease in simulated lake area for the decade 1966–1975, the simulated lake level and area are in better agreement with the observations when irrigation is included. For the period 1983–1994 the observed water use for irrigation increased fourfold compared to 1953–1979. A comparison of the simulated surface water area, with and without irrigation, suggests that climate variability still controls the interannual fluctuations of the water inflow but that human water use accounts for roughly 50% of the observed decrease in lake area since the 1960s and 1970s.