Infrared thermometry allows evaluating water status of the crop by measuring crop water stress index (CWSI), without the need of physical contact to leaves. In order to quantify water stress by CWSI and finding the best irrigation regime a two-year field experiment was conducted in safflower during 2017 and 2018 growing seasons at Darab, Fars province, Iran. Two safflower cultivars (Goldasht and Local Isfahan) and four irrigation regimes consisted of well-watered [Irrigation based on 100% field capacity (FC)], mild (75% FC), severe (50% FC), and most severe (25% FC) water stress were arranged as split plot according to randomized completely block design with four replicates. The relationship between vapor pressure deficit (VPD) and canopy-air temperature differences (Tc-Ta) was plotted under upper (fully stressed) and lower baselines (non-stressed) equations. In two cultivars, by VPD increment, the distance between upper and lower base lines increased. In Goldasht, the upper baseline (Tc-Ta)ul, was 7.8°C in 2017 and 8.9°C in 2018. From April to July when air warmed, Tc-Ta differential was increased up to July and the highest seasonal CWSI (0.72 to 0.77) were obtained in Local Isfahan under most severe water stress. In 2017, under water stress, the highest relative water content (RWC; 55%), color quality (6-7) and water use efficiency (WUE; 2.69 g. m-2. mm-1) was observed in Goldasht under mild water stress which was more than 2018 and Local Isfahan. It might be attributed the more tolerance of Goldasht to water stress and lower air temperature and evaporation in the first year. CWSI with total water consumed (R2= 0.88**), RWC (R2= 0.87**), color quality (R2= 0.75*) and seed yield (R2= 0.83**) related, negatively. Overall, a mild water stress (75% FC) with 0.28 to 0.33 seasonal CWSI had higher RWC, color quality, WUE, with an acceptable yield, which could be the best irrigation regime under water deficit conditions for safflower.