The COVID-19 pandemic has a major impact on mental well-being and interpersonal relationships. Nonetheless, little is known about the complex interactions between one's overall perceived interpersonal closeness and physiological or psychological aspects of interpersonal functioning. This study aimed to understand the interaction between perceived interpersonal closeness during COVID-19 and interpersonal mechanisms in predicting well-being. We focused on two interpersonal mechanisms, one physiological and the other psychological: (a) prepandemic physiological synchrony, a physiological measure of interpersonal coupling, and (b) peripandemic emotional contagion, one's tendency to "catch" others' emotions. One hundred fifty-five participants took part in the study. Cardiological interbeat interval synchrony was collected 1.5 to 3 years prior to the beginning of the COVID pandemic in two previous lab studies. Participants were recontacted during the pandemic, this time to complete several questionnaires tapping into perceived interpersonal closeness, tendency for emotional contagion, and psychological well-being during COVID. As hypothesized, overall perceived interpersonal closeness was positively related to well-being. Moreover, this effect was moderated by one's tendency for emotional contagion or by physiological synchrony. Thus, individuals with higher emotional contagion scores or higher physiological synchrony had higher well-being if their interpersonal closeness was perceived as greater. Conversely, their well-being was lower if they perceived their interpersonal closeness as weaker. These results emphasize that individuals may be differentially susceptible to the effects of their relationships on their well-being. Future mental health interventions should consider both the quality of one's perceived interpersonal closeness and the extent to which one is sensitive to others' emotional experiences.