--- - |2+ Abstract Objective Investigating whether intolerance of uncertainty interacts with difficulties in emotion regulation and negative affect in Italian individuals with borderline personality disorder compared to healthy controls. Method A group of patients with borderline personality disorder (N = 48; clinical group) and a group of healthy participants (N = 48) matched on gender filled‐in self‐report measures assessing difficulties in emotion regulation, intolerance of uncertainty, and negative affect. Results Individuals in the clinical group showed higher levels of difficulties in emotion regulation (except for lack of emotional awareness), intolerance of uncertainty, and negative affect than healthy participants. Interestingly, while difficulties in emotion regulation were correlated with negative affect in both groups, significant medium‐large correlations between difficulties in emotion regulation and intolerance of uncertainty were observed only in the clinical group. Lastly, findings from a stepwise hierarchical multiple regression analysis conducted on the clinical group revealed that difficulties in emotion regulation were the most significant predictors of negative affect above and beyond IU. Conclusions Current findings highlight that difficulties in emotion regulation can be intended as a core, high‐level process underlying borderline personality disorder and that IU might be involved—although more marginally—in predicting negative affect in this population. Future research further exploring whether and how intolerance of uncertainty and difficulties in emotion regulation interact in borderline personality disorder may inform psychological assessment and treatment. - Clinical Psychologist, Volume 22, Issue 2, Page 137-147, July 2018.