In order to investigate the effect of drought stress on some agronomic and physiological traits of safflower, a field experiment was conducted in Agricultural Research Farm of Isfahan University of Technology (Lavrak) located at Najafabad. In this study, 21 safflower genotypes were evaluated at two itrrigation regime of non stress and stress condition by using a randomized complete block design with two replications i growing season of 2018. In this experiment, the traits of days to 50% flowering, days to full flowering, days to maturity, plant height, number of main branch per plant, number of capitula per plant, number of seeds per capitulum, 1000 seed weight, seed oil content, grain yield per plant and grain yield per unit area, RWC, MSI, chlorophyll a and b , and carotenoids concentration were measured. The results showed that the effect of drought stress on all studied traits was significant and the traits of number of heads per plant and chlorophylls a and b concentration were more affected by drought stress than the other traits. Under stress conditions, there was a positive correlation between grain yield per unit area with each of plant height, number of main branch per plant and number of capitula per plant, leaf relative water content, membrane stability and carotenoids content. The results of stepwise regression for grain yield per unit area showed that in non stress conditions, plant height and membrane stability index were entered to the model and explained 70% of its variation.. However, under moisture stress condition, number of capitula per plant, day to 50% flowering, carotenoids content and membrane stability index were more important traits and explained 77% of the grain yield variation. The results of path analysis for grain yield per unit area showed that in both moisture conditions, number of capitula per plant had the most direct and positive effects on grain yield. . The highest indirect and negative effects in stress condition belonged to 1000-seed weight. To determine the drought tolerance of the genotypes, tolerance and sensitivity indices (SSI, TOL, GMP, STI and MP) were calculated. Considering the correlation coefficients, GMP and STI indices were recognized as more suitable indices for determining more tolerant and high yielding genotypes. Also, physiological traits of leaf relative water content and carotenoids content were highly correlated with GMP, STI and MP indices. The biplot diagram showed that genotypes A2 and M420 were more tolerant genotypes with higher yield potential and more leaf relative water content and carotenoid content. Key Words: Genetic Variation, Drought stress, Safflower, Agronomy and Physiological traits