To evaluate the effect of supplemental irrigation on nutrient uptake, water relations and drought tolerance of safflower, an experiment with four levels of irrigation (no irrigation, irrigation at the heading, flowering and both heading and flowering stages) and three safflower cultivars (Gila, Isfahan local and PI-537636) was conducted as a split plot based on randomized complete block design with three replications at Ardebil Agricultural Research Station during 2008. Irrigation showed significant impact on leaf potassium content, relative water content, leaf water potential and membrane stability. There were significant differences amongst cultivars in terms of sodium, potassium, and calcium content, leaf water potential as well as membrane stability and a significant interaction was also observed between irrigation and cultivar on leaf water potential and membrane stability. The highest water potential (-0.57 MPa) and membrane stability (95.3%) was obtained by Gila cultivar when irrigated at heading and flowering stages. PI-537636 genotype showed superiority based on stress susceptibility (SSI) and tolerance (TOL), while Isfahan local variety was superior in terms of the stress tolerance index (STI) and geometric mean productivity (GMP). However, given the fact that the best cultivars are those producing high yields under normal conditions with the minimum yield reduction under drought stress, Isfahan local variety was the preferable cultivar under drought stress conditions.