Objective To study the effect of tumor size on the expression of adrenal cholesterol homeostasis molecules in H22 hepatoma-bearing mice. Methods Two hundred and twenty mice were injected with H22 hepatoma cells to their right armpit. On the 11th day after injection, the mice were sorted according to the tumor size. 18 mice with large tumor (large tumor group) and 18 mice with small tumor (small tumor group) were sacrificed, and the tumors were weighed.A control group consisting of 18 normal Kunming mice was also included in this study. The plasma TC, TG and HDL-C were detected using total cholesterol, triglycerides or HDL-C assay kits, respectively. The mRNA expressions of Srb1、Ldlr、Npc1、Npc2、Stard3、Hmgcr、Lipe、Acat1、Abca1、Abcg1、Srebp-1c、Lxrα、Lxrβ、Rxrα、Apoa1、Apoeand Apoe were tested by real-time quantitative RT-PCR (qRT-PCR), and Gapdh and β-actin were used for normalization. SRB1 and ApoA1 proteins were analyzed by Western blot. Results The tumor weight was significantly higher in the large tumor group than that in the small tumor group (P<0.05). Compared with the control group, the plasma HDL-C was significantly decreased in the two hepatoma groups (P<0.05). The expression levels of Srb1, Ldlr, Apoa1 mRNA and SRB1 protein were significantly increased in the large tumor group (P<0.05 for all). The ApoA1 protein level was significantly higher in the large tumor group than that in the small tumor group (P<0.05). The expressions of Acat1, Lipe, Abca1 and Abcg1 mRNA were significantly lower in the large tumor group than those in the small tumor group (P<0.05 for all). However, the expressions of Srebp-1c, Lxrα and Rxrα mRNA were not significantly changed, then, Srebp-1c, Lxrβ and Rxrα mRNA expressions were significantly up-regulated in the small tumor group (P<0.05). The expressions of Hmgcr and Apoe mRNA were not significantly different in the two groups. Conclusions In hepatoma-bearing mice, due to the adaptation to tumor-induced chronic stress response, the adrenal cortical cells can effectively utilize intracellular cholesterol to synthetize cortical hormones.