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An orthogonal L16(45) design of combined effects of the five factors, nitrogen (N) fertilizer, phosphorus (P) fertilizer, potassium (K) fertilizer, organic manure, and water on the spring wheat (Triticum aestivum L.) yield, has been conducted for three years on Orthic Anthrosols at Shapotou in the southeast margin of the Tengger Desert. The results show that N and P fertilizers have significantly influenced spring wheat yield, that characterized by increase of the yields by increasing applies of N and P fertilizers. If the application rates of N and P fertilizers reach 200 kg ha−1 and 35.6 kg ha−1, the spring wheat yield was the highest. Potassium fertilizer has a less influence on spring wheat yield, suggesting that it is unsuitable to use it in the fertile Anthrosols in the loess region. Irrigation intensity is also a key factor affecting crop production in this arid region. The irrigation intensity in the experimental range is directly proportional to the wheat yield, but lower irrigation intensity has larger yield-increasing efficiency than that of higher irrigation intensity. In addition, the influences of NPK fertilizers on the nutrient contents in soil and spring wheat straw, and the interactions between various fertilizers and water are analyzed. The optimal water–fertilizer combination and maximum production potential were determined by establishing a water–fertilizer–yield model. [ABSTRACT FROM AUTHOR]