Objective To investigate the kidney yang deficiency constitution and hypothalamus-pituitary-adrenal (HPA) axis dysfunction in Lewis rats. Method Two kidney yang deficiency models were established by subcutaneous injection of hydrocortisone and by adrenalectomy to induce hypothalamic-pituitary-adrenal (HPA) axis dysfunction in Lewis rats. Wistar rats were used as control and compared with the two types of Lewis rat models of kidney yang deficiency. The degree of kidney yang deficiency of the Lewis rats was evaluated by examination and detection of the general signs, behavior, and neuroendocrine function, and so on. Result Compared with the normal Wistar rats, the body weight of Lewis rats was significantly higher than that of Wistar rats at the same age. The body temperature, urine volume and grip strength were significantly lower than those of Wistar rats (P<0.01 for all). The memory ability of the Lewis rats was slightly decreased. The liver, kidney and adrenal indexes were significantly decreased in the Lewis rats (P<0.01). The levels of serum ACTH, CRH, cGMP, Cort and urine 17OHCS were significantly decreased (P<0.01). Conclusion A very slight deficiency of adrenal cortex function of Lewis rats is caused by genetic inheritance, and Lewis rats have the constitution of congenital kidney yang deficiency (criticality or prophase of kidney yang deficiency).