Abstract: In order to improve the safety, quality and aroma of Shandong flue-cured tobacco, the effect of four different ratios of cake fertilizer and chemical fertilizer treatments on tissue structure and organic acid contents in the middle leaves of flue-cured tobacco NC102 was investigated by field experiments. The results showed that the middle leaves of the treatment with chemical fertilizer only were significantly smaller than the other treatments that included cake fertilizer, that leaf thickness was increased with increased ratio of cake fertilizer, and that the contents of malic acid, citric acid and oxalic acid in leaves were negatively correlated with the amount of cake fertilizer applied. The tissue structure and organic acid contents in leaves of the treatment with 25% cake fertilizer and 75% chemical fertilizer were better than the other treatments, which indicated that leaves from this treatment had the characteristics of low tar and high flavored tobacco. Under the condition of this study, the 25% cake fertilizer in combination with 75% chemical fertilizer treatment is more conducive to improve the safety, quality and aroma of Shandong flue-cured tobacco.