Psychological and somatic sickness symptoms are common adverse side effects of immunotherapy and chemotherapy. Due to the unpleasantness of these symptoms, many patients develop negative treatment expectations during the course of therapy and often show anticipatory behavioral and physiological responses upon re-exposure to treatment-related cues. Despite broad clinical implications, the underlying molecular and neurobiological mechanisms of sickness-induced negative treatment expectations and their physiological consequences are largely unknown and difficult to study in humans. This calls for translational models that mimic clinically relevant features of negative treatment expectation. Here we present results from an animal model of endotoxin-induced sickness. In an associative learning paradigm in rats, we combined the presentation of an unfamiliar taste (saccharin) with the injection of bacterial endotoxin as sickness-inducing agent. Using this protocol, we were able to establish a negative treatment expectation in rats, which was reflected in a conditioned taste avoidance (CTA). The strength of the CTA increased with the number of prior treatment experiences and was resistant to extinction. This suggests that sickness-related negative treatment experiences form a strong memory trace that is difficult to erase. The endotoxin-induced central inflammatory response during acquisition involved brain regions thought to be involved in the generation and retrieval of negative treatment expectations, including the insular cortex. Re-exposure to the treatment-associated taste stimulus elicited an anticipatory neuroendocrine stress response, suggesting the involvement of the fear-related circuitry. The underlying neurobiological mechanisms are currently being investigated using chemogenetic approaches.