Two field experiments were carried out during the two successive seasons (2007/2008 and 2008/2009) at the experimental station of El Sheikh Zowayed, Desert Research Center to study the effect of biofertilizer application (Azotobacter chrococcum,  Azospirillum lipoferum and mixture of them) under three levels of saline irrigation water (2000, 3000 and 4000 µgl^-1) on growth and productivity of safflower (Carthamus tinctorius L).  The obtained results showed that, biofertilizer treatments significantly increased microbial activities in safflower rhizosphere (total bacterial counts, azotobacters and azospirilla densities, CO₂ evolution and dehydrogenase activity). Also, biofertilizers enhanced plant height, number of branches per plant, fresh and dry weight /plant. On the other hand, nitrogen content in soil and shoots plant at 35, 70 and 120 days from sowing increased by inoculation with biofertilizers during the two seasons. Number of heads /plant, head diameter, number of seeds /head, weight of 100 seed, stand, protein, phosphorus, oil content and oil yield at harvest significantly increased in biofertilizers treatments. Dual inoculation treatment gave the highest values of growth characters, yield and chemical composition of safflower plant as well as microbial activities in safflower rhizosphere. Increasing salinity in irrigation water from 2000 to 4000 µgl^-1 significantly decreased microbial activities in safflower rhizosphere, growth characters, yield, yield components and chemical contents of plant. Interaction between biofertilizer treatments and salinity had a significant effect on microbial activities in safflower rhizosphere. Also, application of dual or individual biofertilizer with saline irrigation water improved plant growth and yield and yield components of safflower compared with uninoculated plants.