The intensive use of N fertilizers to maximize yields increase susceptibility of wheat (Triticum aestivum L.) cultivars to fungi attack. The interaction between N response and fungi infection is well documented in Uruguay for conventionally tilled wheat. Under no-till, crop residues on the soil surface influence plant growth and development, nutrient cycling and uptake, and the incidence and severity of plant diseases. Knowledge of this interaction would assist decision making for fertilizer and fungicide management increasing input efficiency. Field experiments were conducted in INIA-La Estanzuela (Uruguay) during 2003-2004 to assess the agronomic responses of 5 high yielding commercial cultivars to N fertilization and fungal disease control. Treatments consisted of a factorial combination of 4 N doses (up to 210 kg ha^-1), and 3 protection strategies: 1) unprotected crop, 2) total protection, consisting in preventive periodic fungicide applications throughout the growing season, 3) strategic fungicide applications based on disease infection and environmental conditions. Under moderate disease pressure yield increased with fungicide application only in susceptible cultivars. Yield increase was associated with larger grain weight per ear due primarily to heavier 1000-kernel weight. Although N use efficiency in the most susceptible cultivar tended to be higher with total protection at high N rates, differences between total protection and strategic protection were not significant. Under higher disease severity, all cultivars increased their response to N with crop protection. The higher N rate and total protection consistently gave the highest grain yields. Nitrogen use efficiency in the most susceptible cultivar was 7, 18 and 24 kg of grain per kg of applied N, and maximum yields achieved were 4000, 6700 and 7800 kg ha^-1, for non-protection, strategic protection and total protection, respectively. Yield increase due to disease control was associated with more kernels per square meter and heavier 1000-kernel weight. It was concluded that although N response under moderate disease pressure tended to increase in all cultivars following total fungicide protection, the use of fungicide was only economical in susceptible cultivars, and strategic protection would be recommended. Fungicide application was economical in all cultivars when a complex of fungal disease attacked the crop early in the growing season, but total protection was economical only in very susceptible cultivars or when the higher N rate was applied.