Objective To elucidate the onset process and pathological characteristics of spontaneous hindlimb paralysis in a hyperlipidemia-susceptible (WSHc) rat population, and to preliminarily study the pathogenesis mechanism. Methods In a WSHc rat population, eight spontaneous hindlimb paralysis rats and eight age-matched rats without paralysis symptoms from the same family were fed with normal chow or high-fat chow to examine their susceptibility to hyperlipidemia. Magnetic resonance imaging and histopathology were used to examine central neuropathy in different parts of hindlimb paralysis rats. TUNEL immunohistochemistry was used to detect apoptosis. The mRNA expression of Caspase-1 and IL-1β in the central nervous system was determined by RT-PCR, and the corresponding protein expression was determined by Western Blot. Results Both male and female WSHc rats with hindlimb paralysis developed the paralysis. The sensitivity to high-fat diet was not significantly different between WSHc rats with and without hindlimb paralysis. No significant lesions were observed in the brain and cerebellum by magnetic resonance imaging. Histopathology showed a large amount of inflammatory cell infiltration and TUNEL-positive staining in the middle and posterior spinal cord of hindlimb paralysis WSHc rats. Compared with the non-hindlimb paralysis WSHc rats, the mRNA and protein expression of Caspase-1 and IL- 1β in the middle and posterior spinal cord was significantly increased (P < 0. 05, P< 0. 01) in the hindlimb paralysis WSHc rats. Conclusions Spontaneous hindlimb paralysis of hyperlipidemia-susceptible WSHc rats is a progressive lesion, which occurs in the middle and posterior spinal cord and is pathologically featured by inflammatory cell infiltration, neuronal degeneration and apoptosis. This pathogenesis may be related to excessive activation of caspase-1.