© 2015 Elsevier Inc. Neuropsychiatric disorders (e.g., autism, schizophrenia) are partially characterized by social cognitive deficits, including impairments in the ability to perceive others' emotional states, which is an aspect of social cognition known as theory of mind (ToM). There is also evidence that inflammation may be implicated in the etiology of these disorders, but experimental data linking inflammation to deficits in social cognition is sparse. Thus, we examined whether exposure to an experimental inflammatory challenge led to changes in ToM. One hundred and fifteen (n = 115) healthy participants were randomly assigned to receive either endotoxin, which is an inflammatory challenge, or placebo. Participants completed a social cognition task, the Reading the Mind in the Eyes (RME) test, at baseline and at the peak of the inflammatory response for the endotoxin group. The RME test, a validated measure of ToM, evaluates how accurately participants can identify the emotional state of another person by looking only at their eyes. We found that endotoxin (vs. placebo) led to decreases in performance on the RME test from baseline to the peak of inflammatory response, indicating that acute inflammation can lead to decreases in the ability to accurately and reliably comprehend emotional information from others. Given that deficits in ToM are implicated in neuropsychiatric disorders, including those which may have an inflammatory basis, these results may have implications for understanding the links between inflammation, social cognition, and neuropsychiatric disorders. Clinical Trials Registration.