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The response of winter wheat (Triticum aestivum L.) to the application of different rates of nitrogen (N) and phosphorus (P) on different agro-climatic zones (ACZs) has not been well studied in Afghanistan. The objectives of this study were to (1) determine the impact of soil and climate on the responses of wheat to N and P fertilization, (2) quantify the specific N and P response of winter wheat for different ACZs, and (3) determine the economical application rates of N and P for farmers for each considered ACZs. This paper evaluates the effects of nitrogen levels (NL) at 35.28, 65, 95, and 120 kg N ha−1 and phosphorus levels (PL) at 0, 50, 70, and 90 kg P2O5 ha−1, respectively, in four locations (L) for two growing seasons (GS), on both yield and quality characteristics of winter wheat. Soil pH was the main environmental parameter affecting straw yield (SY), grain yield (GY), protein content (PC), and protein yield (PY). Winter wheat SY, GY, PC, and PY increased significantly (p < 0.05) with PL rates up to 50 kg P2O5 ha−1 and with NL rates up to 120 kg N ha−1. NL was the most important parameter in determining PC, thus showing potential for further improvement in N management. The highest marginal rate of return was used as an index for the farmers to accept site-specific N and P fertilizer recommendations. [ABSTRACT FROM AUTHOR]