The High Plains Aquifer is the source of nearly all agricultural irrigation water in the Texas High Plains, and its resources are being depleted due to withdrawals that greatly exceed recharge; therefore, expanding the use of deficit irrigation in this region. Some drought-tolerant crops, including cotton (Gossypium hirsutum L.), can adapt well to deficit irrigation, but this adaptation might be cultivar- and environment-specific. The objective of this study was to determine if the response of commercially available cultivars to differential irrigation was influenced by the environment. Seven cotton cultivars (DP0912B2RF, DP0924B2RF, DP0935B2RF, DP1028B2RF, DP1032B2RF, DP1044B2RF, and FM9160B2F) were evaluated in 2010 and 2011 at three irrigation levels, ranging from severe-deficit to full irrigation in West Texas. In-season soil moisture content, yield, and water use efficiency were compared by cultivar and irrigation level. In 2010, which was wet and cool, the earlier-maturing cultivars, particularly DP0912B2RF, performed favorably compared to the later-maturing cultivars at the highest irrigation levels. In 2011, which was hot and dry, later-maturing cultivars, such as DP1044 and DP0935, had the highest yields. There was also a strong interaction between study year, irrigation rate, and cultivar performance. In 2010, later-maturing cultivars such as DP0935 and DP1044 had lower yields at the highest irrigation, but higher yields in the deficit treatments. DP1044, the latest maturing cultivar in the study, was a top yielding cultivar in both seasons, suggesting that a cultivar with later maturity characteristics can be successful in both hot and heat-limited environments on the Texas High Plains.