Field studies were conducted on Sharkey clay soil (very-fine, smectitic, thermic Chromic Epiaquert) at Stoneville, MS (33°26′ N lat). The objectives were to determine the effect of application of 0 and 35 kg N ha−1 applied early in the growing season to glyphosate-resistant (GR) and non-GR soybean [Glycine max (L.) Merr.] cultivars using two weed management systems in irrigated and nonirrigated environments. Weed management systems were (i) pre-emergent followed by postemergent weed management using nonglyphosate herbicides applied to both GR and non-GR cultivars (PRE + POST) and (ii) postemergent weed management using glyphosate on GR cultivars and nonglyphosate herbicides on non-GR cultivars (POST). Applied N had no effect on weed management in or yield from soybean and lowered average net returns by $28 to $50 ha−1. Average seed yields from the highest-yielding GR cultivar in 1999 and 2000 were 135 and 270 kg ha−1 more than 1999 and 2000 yields from a non-GR cultivar in the nonirrigated environment (all net returns were negative and yields <1500 kg ha−1). In the irrigated environment, use of a non-GR cultivar compared with a GR cultivar resulted in a significant 200 and 250 kg ha−1 greater yield and greater profits in 2 of 3 yr. Use of PRE + POST compared with POST-only was not necessary for achieving greatest yield or net return with either non-GR or GR cultivars. Use of postemergent glyphosate always resulted in the cheapest weed control ($43 to $81 ha−1), even with the greater cost for seed of GR cultivars included. There was no measured effect of glyphosate compared with nonglyphosate herbicides on GR cultivar yield.