Wheat is the main cereal crop in Egypt. The gap between production and consumption is about 60%. Research efforts are needed to reduce this gap, therefore; the objective of this work was to study the effect of three water regimes as irrigation at 45%, 60% and 70% depletion of the available soil moisture, and three nitrogen fertilization levels on two wheat varieties (Giza 168 and Giza 171).The field experiments were carried out at Bahry El-Methaq region, Alexandria Governorate, Egypt during the two successive winter seasons of 2015/2016 and 2016/2017. The experimental design of the study followed split split plot design (SSPD) with three replicates, keeping two bread wheat cultivars {Giza 168 and Giza 171 } as the main plots, irrigation regimes (irrigation at 45%, 60% and 70% depletion of the available soil moisture) as subplot, and the three fertilization levels as 100%, 80% and 60% from recommended fertilizer rates of nitrogen fertilization common applied as sub-subplot. The results showed that seasonal ET0 was 665.9 mm for the first season and 624.8 for the second season. Wheat crop transpiration was 600.28 mm at 2015-2016 growing season and 572.95 mm for the next season. The seasonal applied irrigation water in total was 2702.2 m3, 2792.6 m3 and 2879.1 m3 at 45%, 60% and 70% depletion treatments for 2015-2016 growing season, respectively. The corresponding values for the next growing season were changed to 2802.5 m3, 2687.4 m3 and 2716.4 m3. Based on the irrigation regimes and water balance by the budget technique, the irrigation events of wheat at 45%, 60% and 70% depletion treatments were 29, 23 and 21, which required irrigating for 23.17, 23.94 and 24.69 hours in the first season, respectively. The second season results changed to 28, 23 and 20 irrigations, which required irrigating for 24.4, 22.96 and 23.29 hours. The results indicated that the maximum grain yield and water use efficiency of wheat regardless of the variety under investigation could be obtained with irrigation at 60% depletion of the available soil moisture and 100% of the recommended nitrogen fertilization. The yield and water use efficiency of Giza 168 under these conditions were 2.78 ton/fed and 1.02 kg/m3. While for Giza 171, 3.4 ton/fed and 1.24 kg/ m3 were obtained with 22.3% and 21.6% increase in yield and water use efficiency, respectively.The results indicated a significant effect of crop cultivars and nitrogen fertilization levels on biological yield, straw yield, grain yield, WUE of grain yield and WUE of straw yield. Meanwhile, irrigation regimes showed insignificant effect on the previous parameters. The interaction of wheat cultivars, nitrogen fertilization levels and irrigation water regime levels showed insignificant effect on biological yield, straw yield, grain yield, WUE of grain yield and WUE of straw yield.