The use of cytotoxic substances, such as 5-fluorouracil and cyclophosphamide, is carefully controlled; however, these medications may still enter bodies of water through wastewater discharge. These substances may pose risks to stream and river life, as well as to humans via drinking water. In this study, the photochemical fate of 5-fluorouracil and cyclophosphamide was investigated in synthetic waters and four river waters and was found to be the most important attenuation process for each entity in natural surface waters. Bicarbonate alone was found to react with the excited states of 5-fluorouracil, thus enhancing direct photolysis rates. In the presence of nitrate and significant amounts of bicarbonate (close to 2 mM), 5-fluorouracil was rapidly removed (within 1 day) through indirect photolysis. In contrast, natural attenuation was of low importance for cyclophosphamide in most surface waters studied. A long, shallow river or lake with a long residence time (>7 days), very low alkalinity, and significant nitrate levels (>5 mg-N L(-1)) may be an exception. The phototransformation product of 5-fluorouracil was also identified. However, the total organic carbon experiments yielded important results: photolysis resulted in quick transformation of 5-fluorouracil but minimal mineralization. Additional studies of the toxicity of photobyproducts of 5-fluorouracil are needed to determine the true risk to human health of 5-fluorouracil contamination of surface water, given its near-total photodegradation and resultant, deceptively low detection rate in surface waters.