Greenhouse and field studies were conducted to determine the influence of herbicide rate, hybrid variability, and soil moisture on the effectiveness of CGA-154281 in protecting corn seedlings from metolachlor injury. High rates of metolachlor caused significant injury to seedlings of sensitive corn hybrids. However, with metolachlor plus CGA-154281, very few injury symptoms were observed, even with the 7.8 kg ha–1 rate and the most sensitive hybrid. Corn seedlings were not injured by metolachlor plus CGA-154281 at the highest soil moisture level evaluated, whereas those treated with metolachlor alone showed 70% injury. Metolachlor injury increased as soil moisture content increased. In the greenhouse, CGA-154281 did not protect any of the eight weed species tested against injury by 2.2 kg ha–1 metolachlor. In laboratory studies, CGA-154281 did not alter the absorption of 14C-metolachlor during an 8-h period. Qualitative comparison of the metabolism of metolachlor in the presence or absence of the protectant indicated that metolachlor was metabolized to a more polar metabolite, believed to be a glutathione conjugate. However, CGA-154281 significantly enhanced the rate of metabolism of metolachlor in three of the four hybrids tested. Metolachlor metabolism activity may already have been functioning at a maximum level in the unaffected hybrid.