BACKGROUND: A population of waterhemp in a seed maize production field in central Illinois, United States, was not adequately controlled after post-emergence applications of herbicides that inhibit 4-hydroxyphenylpyruvate dioxygenase (HPPD). RESULTS: Progeny from the field population survived following treatment with mesotrione, tembotrione or topramezone applied to the foliage either alone or in combination with atrazine in greenhouse experiments. Dose-response experiments indicated that the level of resistance to the HPPD inhibitor mesotrione is at least tenfold relative to sensitive biotypes. CONCLUSION: These studies confirm that waterhemp has evolved resistance to HPPD-inhibiting herbicides.