Background/ObjectiveIn this study a theoretically driven model is presented of how gastrointestinal anxiety, behavioural response, symptom severity, quality of life and IBS acceptance interact to determine how people cope and respond in IBS. MethodCross-sectional data from 166 outpatients attending a motility disorders clinic was used to test a model of moderated serial mediation. ResultsGastrointestinal anxiety and behavioural response were found to serially mediate the relationship between symptom severity and quality of life; each step of this ‘indirect effect’ was significant at the p < .001 level. The strength of the mediatory effect was linearly related to IBS acceptance; a significant interaction was found between IBS acceptance as a moderator at the level of the indirect effect (−0.0091, 95%CI = −0.0163 to 0.0019). ConclusionsFindings suggest that the effect of multiple psychosocial variables in IBS experience and outcomes may be conditional on levels of IBS Acceptance. The theoretical and clinical implications of these findings are discussed.