Drought stress is a major abiotic factor causing yield loss in safflower and limited studies have been carried out to dissect the molecular mechanism at EST-SSR level. In this study, a possible relationship between simple sequence repeats (SSRs) distribution and drought stress was studied using three EST libraries of safflower, Ct-D-EST, Ct-NEST and Co-EST. The Ct-D-EST was generated from drought tolerant safflower cultivar A-1; Ct-NEST and Co-EST were the EST datasets of safflower and its wild progenitor C. oxycanthus, respectively. In total, 156 (45%), 1194 (5%) and 1550 (9%) EST-SSRs were mined from Ct-D-EST, Ct-NEST and Co-EST libraries, respectively. Comparison of EST-SSRs from Ct-D-EST with that of SSRs from other two libraries showed reasonable differences for each class of repeats. Large variations were observed for dinucleotide repeats in all the libraries. In drought EST-SSRs, only one kind of amino acid was produced by repeat (ATG) 14 which encodes met indicating the loci and repeat observed to be 100%. Since three ESTs with SSRs from Ct-D-EST, annotated to putative candidate genes, S-adenosylmethionine synthetase, one-helix protein and myo-inositol 1-phosphate synthetase, did not express with SSRs in the Ct-NEST , these can be considered as potential candidate genes for drought tolerance. A trinuceotinde SSR, encoding met, was also found in the EST annotated to putative s-adenosylmethionine synthetase, hence, both can be considered as indices for drought tolerance. The genomic resources and the information generated in this study may be useful for the safflower breeders particularly for the development of drought tolerant cultivar.