Abstract Although research has established links between feelings of social isolation and inflammation, the direction of these effects is unclear. Based on the role that proinflammatory cytokines play in initiating “sickness behavior,” which includes symptoms such as social withdrawal, it is possible that inflammatory processes heighten feelings of ‘social disconnection.’ Here, we examined whether exposure to an inflammatory challenge increased self-reported feelings of social disconnection. In addition, because both inflammatory processes and feelings of social disconnection contribute to depressive symptoms, we also explored whether increases in feelings of social disconnection played a role in the link between inflammation and depressed mood. Participants were randomly assigned to either receive endotoxin, an inflammatory challenge, or placebo. Proinflammatory cytokines (IL-6, TNF-α) were collected at baseline and then hourly for 6 h. Participants completed self-reports of sickness symptoms (“fatigue”), social disconnection (“I feel disconnected from others”), and depressed mood (“unhappy”) hourly. Results revealed that endotoxin led to significant increases (from baseline) in IL-6 and TNF-α levels as well as feelings of social disconnection and depressed mood. Moreover, controlling for increases in social disconnection eliminated the relationship between exposure to inflammatory challenge and depressed mood. This study demonstrates that inflammation can have social psychological consequences, which may play a role in cytokine-related depressive symptoms.