ABSTRACT Background: Illness perceptions (IPs) and avoidance behavior both predict quality of life (QoL) in people with irritable bowel syndrome (IBS). This study examined whether the effects of IPs on QoL are mediated by avoidance behaviors, and whether this mediation is moderated by participant treatment-seeking status. Methods: People with self-reported IBS (n = 253) answered a survey assessing QoL, IPs, avoidance behaviors, and treatment-seeking status. Moderated-mediation analyses investigated the paths from IPs through avoidance behaviors to QoL, with treatment-seeking status entered as a moderator. Results: The final moderated mediation model included the IPs consequences, timeline and emotional representations as independent variables and avoidance behavior and depressive reactions as mediators. This model explained 68.6% of the variance in QoL. Among treatment-seeking participants five significant mediation effects were found, whereas only one significant mediation effect was found among participants who did not report seeking treatment. Conclusions: IPs seem to drive avoidant behavioral responses to IBS symptoms, which in turn predict reductions in QoL. These relationships seem more pronounced among people who seek treatment for their symptoms. In practice, health care practitioners might help improve the QoL of people with IBS by preventing or remedying the development of negative IPs and avoidance behaviors.