A multiple regression model was applied to annual time series data (1936–1998) in an attempt to quantify the influence of irrigation wells on annual streamflows of Frenchman Creek in Southwestern Nebraska where intensive well development has taken place since 1950. A strong statistical relationship was found between the logarithm of streamflow and number of wells, current and lagged annual precipitation, and two variables that are the geometric mean of precipitation and number of wells in the current year and the year before last. Estimated mean streamflow from the statistical model in 1998 is approximately one third of that in 1950. A simpler model without the interaction terms between number of wells and precipitation was estimated for the Republican River near its final entry into Kansas from Nebraska, and an even greater decline in mean annual streamflow was found. The present mean is approximately one quarter of the 1950 level.