Chlorophenoxy herbicides are used both in cereal grain agriculture and in nonagricultural settings such as right-of-ways, lawns, and parks. Minnesota, North Dakota, South Dakota, and Montana grow most of the spring and durum wheat produced in the United States. More than 90% of spring and durum wheat is treated with chlorophenoxy herbicides, in contrast to treatment of approximately 30% of winter wheat. In this ecologic study I used wheat acreage as a surrogate for exposure to chlorophenoxy herbicides. I investigated the association of chlorophenoxy herbicides with cancer mortality during 1980-1989 for selected counties based on level of agriculture ([greater and equal to] 20%) and rural population ([greater and equal to] 50%). Age-standardized cancer mortality rates were determined for grouped counties based on tertiles of wheat acreage per county or for individual counties for frequently occurring cancers. The cancer sites that showed positive trends of increasing cancer mortality with increasing wheat acreage were esophagus, stomach, rectum, pancreas, larynx, prostate, kidney and ureter, brain, thyroid, bone, and all cancers (men) and oral cavity and tongue, esophagus, stomach, liver and gall bladder and bile ducts, pancreas, cervix, ovary, bladder, and other urinary organs, and all cancers (women). Rare cancers in men and women and cancers in boys and girls were studied by comparing counties above and below the median of wheat acreage per county. There was increased mortality for cancer of the nose and eye in both men and women, brain and leukemia in both boys and girls, and all cancers in boys. These results suggest an association between cancer mortality and wheat acreage in counties of these four states.