Anticipatory nausea is a classically conditioned response to a context that has been previously paired with toxin-induced nausea and/or vomiting. When injected with a nausea-inducing drug, such as lithium chloride (LiCl), rats will show a distinctive conditioned gaping response that has been suggested to be an index of nausea. Previous studies have found that immune system activation with an endotoxin, such as lipopolysaccharide (LPS), attenuates LiCl-induced conditioned gaping in rats. The present study examined the acquisition of LiCl-induced conditioned gaping in rats that were either LPS tolerant or LPS non-tolerant, as little is known about the effects of endotoxin tolerance on learning and memory. Male Long-Evan rats were given four systemic injections of LPS (200 μg/kg) or isotonic saline (NaCl) to induce LPS tolerance, indexed with 24 h changes in body weight following treatment. The animals were then given 4 acquisition trials in a LiCl-induced conditioned gaping paradigm. On conditioning days animals were treated with LPS (200 μg/kg) or saline followed 90 min later by injection of LiCl (127 mg/kg) or saline and then placed in a distinctive context for 30 min and their behavior video-recorded. On a drug free test day all animals were again placed in the distinctive context for 10 min and behavior was video-recorded. Gaping responses were scored for all acquisition days and the test day. Spleen and body weights were also obtained for all rats at the end of the experiment. Gaping responses were attenuated in rats treated with LPS in both the LPS tolerant and LPS non-tolerant groups. There were significant negative correlations between spleen weight as well as spleen/body weight ratios, and levels of conditioned gaping responses in LiCl treated rats, but not control rats. These results show that LPS interferes with learning/memory in the anticipatory nausea paradigm in rats that are both LPS tolerant and LPS non-tolerant.