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In this paper, a sequence (1979–2022) of a long-term trial established in Lukavec in 1956 (Czech Republic) focusing on the effect of weather, various nitrogen (N) fertilization methods (control, PK, N1PK, N2PK, and N3PK) and preceding crops (cereals, legumes, and oil plants) on winter wheat grain yield is presented. The weather significantly changed at the site of the long-term trial. While the trend in the mean temperature significantly increased, precipitation did not change significantly over the long term. Four relationships between weather and grain yield were evaluated to be significant: (a) the mean temperature in February (r = −0.4) and the precipitation in (b) February (r = −0.4), (c) March (r = −0.4), and (d) May (r = 0.5). The yield trends for all the fertilizer treatments increased, including the unfertilized control. The N3PK treatment provided the highest mean grain yields, while the unfertilized control had the lowest yields. Comparing the preceding crops, the highest yields were harvested when the wheat followed the legumes. On the other hand, the cereals were evaluated as the least suitable preceding crop in terms of grain yield. According to the linear-plateau model, the optimal nitrogen (N) dose for modern wheat varieties, following legumes and under the trial's soil climate conditions, was 131 kg ha−1 N, corresponding to a mean grain yield of 8.2 t ha−1. [ABSTRACT FROM AUTHOR]