Safflower is a deep rooted drought tolerant crop that originated in desert environments of the Middle East, and could be very well adapted to the semi-arid agriculture in Southern High Plains. A field experiment was conducted at Clovis, NM during 2012 and 2013 seasons to assess drought physiology and yield formation of two diverse spring safflower cultivars under different irrigation levels with or without pre-irrigation. Half of experimental blocks were pre-irrigated (PI) with 160 mm of water to fill the soil profile emptied by the previous crop of corn, while other half remained depleted (NPI). In-season irrigation levels used were I₁ (75 mm), I₂ (150 mm), I₃ (225 mm), I₄ (300 mm) and I₅ (375 mm).  The presentation includes only the first year results of the study here. Increased water availabilities either by higher irrigation levels or by PI reduced water stress (WP) in safflower during two observation dates. However, relative water content (RWC) was only affected by in-season irrigation levels. Transpiration rate (TR) of safflower increased with increased water availability, while photosynthesis rate (Pn) responded only to irrigation levels, but not to PI. Pre-irrigation increased seed yield by 39% over NPI, while I₅ irrigation level increased seed yield by 85% over I₁. Seed yield increase with irrigation levels was gradual, and no difference was observed between I₄ and I₅. Interaction effects and cultivar effects were generally not significant.   Lower stress, higher transpiration, and higher photosynthesis were driving factors for increased productivity of safflower under higher water availabilities. Pre-irrigation improved WUE of safflower over no pre-irrigation, but irrigation levels had no effect on WUE. Number of heads per plant, and seeds per head but not thousand seed weight were driving seed yield increase under increased water availability. Although oil content decreased slightly at higher irrigation levels, oil yield was higher with PI or higher irrigation levels due to higher seed yield.