This study was conducted to assess the tolerance to drought stress in F3 families derived from a cross between cultivated (Carthamus tinctorius ) and wild (C.oxyacanthus) safflower using agro-morphological and physiological traits. The experiment was conducted at Isfahan University of Technology Research Farm in 2011. In total, 41 F3 families along with the two parents were evaluated under drought stress and non-stress field environments using a randomized complete block design with three replications. Fisher and Murrer Stress Sensitivity Index (SSI), Tolerance Index (Tol), Rosille and Hemblin Productivity (MP), Geometric Mean Productivity (GMP) and Fernandez Stress Tolerance Index (STI) were used to compare reaction of genotypes in the two moisture conditions. Phenotypic and genotypic coefficients of variation showed that there is considerable variation between the different families for all the measured traits. Under stress conditions phenotypic and genotypic coefficients, heritability and the range reduced for most traits studied. Results of analysis of variance showed that there was significant difference among families for all traits. Drought stress significantly decreased all traits except that of proline content and chlorophyll (a/b) ratio. Presence of significant genotype by environment interaction for some traits implied different reactions of families to normal and water stress conditions. Under stress conditions, the number of heads per plant, the number of seeds per head, and 1000-seed weight and under no-stress condition the number of heads per plant and the number of seeds per head had the highest significant positive correlation with the grain yield. Stepwise regression results revealed that the number of heads per plant, the number of seeds per head, and 1000-seed weight had the greatest contribution in justifying grain yield under both stress and no-stress conditions. According to the results of path analysis for stress condition, the number of heads per plant and for none-stress condition the number of seeds per head had the most direct positive effect on seed yield per plant. Factor analysis revealed six hidden factors justifying 81% of all variations under normal and 83% under drought stress conditions. Cluster analysis results for both moisture levels grouped the familes into two cluster. Results indicated that the Stress Tolerance Index (STI) and Geometric Mean Productivity (GMP) are effective selection criterion for identification of tolerant genotypes. Based on these indices family 6 and 33 were the most tolerant genotypes. Biplot analysis based on principal component analysis introduced families 6, 33, 36 and 15 as the best performing families under stress and none stress conditions, since they had higher yield potential and were less sensitive to drought stress. In general, the results showed that the F3 generation derived from a cross between cultivated and wild safflower, brings the possibility of selecting drought tolerant families. Key words : Carthamus tinctorius , Carthamus oxyacanthus , Inter-specific hybridization species, drought tolerance index