Decades of research show that people's social lives are linked to their well-being. Yet, research on the relationship between social interactions and well-being has been largely inconclusive with regard to the effects of person-situation interactions, such as the interplay between contextual factors (e.g., interactions occurring in physical vs. digital contexts, different interaction partners) and dispositional tendencies (e.g., Big Five personality traits). Here, we report on exploratory and confirmatory findings from three large studies of college students (Study 1: N = 1,360; Study 2: N = 851; Study 3: N = 864) who completed a total of 139,363 experience sampling surveys (reporting on 87,976 social interactions). We focus on the effects of different modes of communication (face-to-face [FtF] interactions, computer-mediated communication [CMC], and mixed episodes [FtF + CMC]), and types of interaction partners (close peers, family members, and weak ties). Using multilevel structural equation modeling, we found that FtF interactions and mixed episodes were associated with highest well-being on the within-person level, and that these effects were particularly pronounced for individuals with high levels of neuroticism. CMC was related to lower well-being than FtF interactions, but higher well-being than not socializing at all. Regarding the type of interaction partner, individuals reported higher well-being after interactions with close peers than after interactions with family members and weak ties, and the difference between close peers and weak ties was larger for FtF interactions than for CMC. We discuss these findings with regard to theories of person-situation interactions and research on well-being and social interactions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).