Using alternative water resources such as agricultural drainage water is considered very important to produce crops (e.g., lettuce plant) due to fresh irrigation water shortage, especially in arid and semiarid regions like Egypt. Moreover, production of lettuce hydroponically in economical scale is becoming popular in drought prone areas with less water consumption. This study aimed to explore the effects of irrigation with different combinations of Agricultural Drainage Water (ADW) and fresh water on lettuce (Lactuca sativa L.) yield, quality, and water use efficiency (WUE) under hydroponic conditions. Three combinations were applied as: T1, (100% agricultural drainage water), T2, (50% agricultural drainage water + 50% fresh water), T3, (100% fresh water). Nutrient Film Technique (NFT) hydroponic system was developed with three pipes and nutrient solution added in rates of 12.5%, 50%, and 100% from standard nutrient solution for T1, T2, and T3, respectively. It seems that lettuce plant can be produced in 50 days from planting to harvest the entire system. T2 treatment was effective in increasing the green and dry matter yields, where the green yields accounted for 2.330, 10.587, and 7.090 kg/m²for T1, T2, and T3, respectively. The highest lettuce yields as affected by water treatments could be ranked as follow T2 >T3>T1. This may be attributed to nutritive value of ADW especially at 50% treatment. Moreover, plants irrigated with T2 have ability to use irrigation water more efficiently than those irrigated with other water treatments. Water Use Efficiency values (WUE) were 8.96, 39.215, and 24.451 kg/m³ for T1, T2 and T3, respectively.  Mineral nutrient contents of N, P, K, and Ca in dry matter were obviously higher in plants irrigated with T3 than other water treatments. This may be due to nutrient solution concentration rates.  Heavy metals (Cd, Ni, Cr and Pb) contents in lettuce shoots were higher in plants irrigated with T2 than those irrigated with other water treatments, but their levels did not exceeds the critical levels noted by FAO for edible crops. In conclusion, the NFT hydroponic lettuce could be irrigated safely with agricultural drainage water (ADW) mixed with fresh water in ratio of (50%: 50%) (T2) to produce remarkable economical yield with less water requirement. Moreover, use of agricultural drainage water (ADW) in irrigation of lettuce in hydroponic system could be considered as useful alternative source of wastewater without environmental risk of heavy metals accumulation in soil.