Field studies were conducted in 1999 and 2000 at Belleville, IL, to compare herbicide efficacy and economic return on investment (EROI) for various herbicide systems in conventional, imidazolinone-resistant, glufosinate-resistant, and glyphosate-resistant corn hybrids. Corn injury 14 d after RPA 201772 preemergence (PRE) treatments ranged from 0 to 10%. Treatments with nicosulfuron + rimsulfuron + atrazine injured corn 5 to 24% at 7 d after treatment (DAT); however, no injury was visible at 14 DAT. Corn injury by all herbicide treatments dissipated by 28 DAT. All treatments controlled giant foxtail at least 88%. Common waterhemp was controlled at least 94% with all treatments, except for imazethapyr + imazapyr postemergence (POST), which did not control common waterhemp. All treatments controlled at least 92% of common cocklebur, giant ragweed, and ivyleaf morningglory, with the exception of the total PRE herbicide system of S-metolachlor + atrazine in 2000. Average grain yield ranged from 7,290 to 9,180 kg/ha in 1999, with the yield of the glyphosate-resistant hybrid lower than that of all other hybrids. In 2000, average grain yield ranged from 8,440 to 11,520 kg/ha, with the grain yield of the glyphosate-resistant hybrid greater than that of all other hybrids. There were no differences in economic return in 1999 because of the treatment, the herbicide system, or the hybrid. In 2000 EROI was greater with the glyphosate-resistant hybrid than with the other hybrids. EROI was influenced more by the grain yield of the corn hybrid than by the associated weed control costs. It has been demonstrated by this research that effective and economical weed control can be achieved in all hybrids, with minimal injury.