This study was conducted to determine the effects of inter-row and intra-row spacing on two safflower cultivars under the Eastern Mediterranean conditions in Hatay, Turkey during 2010-2011 and 2011-2012 growing seasons. The field experiments were laid out in a split split plot design with three replications with two cultivars (Dincer and Remzibey) as a main plot, four inter-row spacing (15, 30, 45 and 60 cm) as sub-plot and three intra-row spacing (5, 10 and 15 cm) as sub-subplot. Seed yield and yield-related traits were lower in both cultivars in 2012 comparing to previous year probably due to lower rainfall. Two years’ data indicated that cultivars, inter-row and intra-row spacing significantly affected growth, yield and yield components of safflower. Increasing plants population reduced yield components and yield of individual plants, but increased yield per unit area. Low plant density resulted in significantly higher branches/plant, heads/plant, seeds/head. The highest seed yields per hektare were obtained with sowing safflower cultivars at 5 cm intra-row spacing in 45 cm spaced rows in 2011, and in 30 cm spaced rows in 2012. Our results indicated that higher plant density can be advantageous under yield limiting conditions while sowing winter safflower at 45 x 5 cm inter- and intra-row spacing can be recommended for regular seasons in Mediterranean-Type Environments.