Due to the limited genetic diversity of domesticated species and genetic erosion of crops in recent years, using wild species as an important source of useful genes, is necessary in plant breeding. This study aimed to evaluate genetic diversity and drought tolerance of F4 lines derived from inter-specific hybridization of Carthamus tinctorius × Carthamus palaestinus briefly IP, Carthamus tinctorius × Carthamus oxyacanthus briefly IO and Carthamus palaestinus × Carthamus oxyacanthus briefly PO. All the genotypes were evaluated in two water environments of non-stress and drought-stressed according to a simple lattice design (13×13) with two replications in each environment. The results showed that there was considerable variation among and within crosses for all of the traits indicating that selection for these traits can be effective to produce lines with better performance and quality. The results showed that drought stress had significant effect on all traits except heading date, day to flowering and malondialdehyde (MDA). Significant difference were observed between crosses of F 4 for all traits except weight of heads per plant, relative water content, ascorbate peroxidase and catalase. In this study most decreasing effect by drought was observed for number of head per plant (54.35 %) and the less one was observed for guaiacol peroxidase (137%). The comparison means among crosses showed that IP had the highest yield and had the less day to flowering and IO had the highest oil content. For yield and yield components, crosses IP and IO, showed the lowest decreasing percentage under drought conditions indicating more stability. The results showed some correlations between yield and physiological traits indicating that indirect selection might be useful to improve the performance of these traits. Based on tolerance indice (STI) and yield stability indice (YSI), the cross of IP recognized as the most stable and most drought tolerant. In each of the crosses genotypes with high-performance and oil content were identified. Based on principal component analysis, in the cross of IP, in non-stress and drought, genotypes 38, 54. and 64, in the cross of PO, in non-stress, genotypes 79, 119, 120, 112 and in stress, genotypes 68 and 112 and in the cross of IO, in non-stress and drought, genotypes 136, 137 and 152 were introduced as superior genotypes for future studies. Keywords: Safflower, 4 th generation, inter-specific hybridization, drought