Background <p>Social exclusion, whether due to physical isolation or the subjective perception of being ignored and unwanted, threatens the fundamental human need for social belonging and is experienced as social pain. While its detrimental effects on mood disorders are well documented, its impact on individuals living with chronic pain remains largely unexplored. This study investigates emotional responses to social exclusion in individuals with chronic pain (CPs) compared to healthy controls (HCs), considering the role of comorbid mood disturbances. It also examines whether behavioral and social functioning, across cognitive and psychological domains, modulate the experience and impact of social exclusion.</p> Methods <p>We recruited 38 CPs and 38 HCs, grouped according to validated cut-offs on the Hospital Anxiety and Depression Scale as follow: 22 Normal-CPs (G1), 16 Altered-CPs (G2), 22 Normal-HCs (G3) and 16 Altered-HCs (G4). All participants completed the Cyberball task, a virtual ball-tossing game designed to simulate social inclusion (control condition) and exclusion (ostracism condition) by manipulating the distribution of ball tosses. After each condition, participants reported their mood, emotional state, and perceived threat to psychological needs. Additional assessments included pain intensity, coping strategies, social functioning, and social cognition.</p> Results <p>All groups were matched for age, sex, education, and cognitive efficiency. Participants with mood alterations (G2 and G4) reported higher levels of loneliness than the other groups. All CPs showed higher levels of catastrophizing compared to HCs. In the Cyberball task, all participants felt more excluded in the exclusion condition than in the inclusion condition, indicating decreased well-being following ostracism. Notably, only Altered-CPs exhibited blunted emotional reactivity after exclusion. Compared to HCs, Altered-CPs reported lower self-esteem, reduced happiness, and greater negative affect even during the inclusion condition. Correlation analyses revealed that psychological responses to social exclusion in CPs were associated with mood symptoms, catastrophizing, loneliness, and perceived social isolation.</p> Conclusion <p>These findings suggest that chronic pain, particularly when accompanied by mood disorders, alters emotional processing and increases sensitivity to social context, even in neutral or positive social situations. Addressing social functioning may be crucial for developing personalized and effective treatment strategies for chronic pain.</p> Graphical Abstract <p></p>