Drainage from heavily cultivated soils may be contaminated with U that is leached from the soil or added as a trace constituent of PO4-based commercial fertilizer. The effect of decades-long application of U-rich fertilizer on the U concentration of irrigation drainage was investigated in a small (14.2 km2) drainage basin in southeastern Colorado. The basin was chosen because previous reports indicated locally anomalous concentrations of dissolved NO3(6-36 mg l-1) and dissolved U (61 ??g l-1) at the mouth of the only stream. Results of this study indicated minimal impact of fertilizer-U compared to natural U leached from the local soils. Detailed sampling of the stream along a 6 mile (9.7 km) reach through heavily cultivated lands indicated marked decoupling of the buildup of dissolved NO3 and U. Dissolved U increased markedly in the upstream half of the reach and correlated positively with increases in Na, Mg, SO4, B and Li derived from leaching of surrounding shaley soils. In contrast, major increases in dissolved NO3 occurred farther downstream where stream water was heavily impacted by ground water return from extensively fertilized fields. Nitrogen isotopic measurements confirmed that dissolved NO3 originated from fertilizer and soil organic N (crop waste). Uranium isotopic measurements of variably uraniferous waters showed little evidence of contamination with fertilizer-derived U of isotopically distinct 234U/238U alpha activity ratio (A.R. = 1.0). Leaching experiments using local alkaline soil, irrigation water and U-rich fertilizer confirmed the ready leachability of soil-bound U and the comparative immobility of U added with liquid fertilizer. Relatively insoluble precipitates containing Ca-P-U were formed by mixing liquid fertilizer with water containing abundant dissolved Ca. In the local soils soluble Ca is provided by dissolution of abundant gypsum. Similar studies are needed elsewhere because the mobility of fertilizer-derived U is dependent on fertilizer type, porewater chemistry and soil properties (pH, moisture, mineralogy, texture).