Social exclusion triggers aversive reactions (e.g., increased negative affect), but being excluded may bring substantial benefits by reducing pathogen exposure associated with social interactions. Is exclusion less aversive when cues of infectious diseases are salient in the environment? We conducted two preregistered experiments with a 2 (belonging status: included vs. excluded) × 2 (disease salience: low vs. high) design, using scenarios (Study 1, N = 347) and a well-validated exclusion paradigm, Cyberball (Study 2, N = 519). Positive affect and negative affect were measured as the key outcomes. Across the 2 studies, we found little evidence that disease salience moderated the effect of exclusion (vs. inclusion) on positive affect. At the same time, we observed consistent evidence that disease salience moderated the effect of exclusion (vs. inclusion) on the other affective component: negative affect. Concretely, disease salience increased participants' negative affect in inclusion conditions; in exclusion conditions, the effect of disease salience on negative affect was negligible or nearly zero. Using a novel and robust approach of mediation analysis (interventional indirect effects), we further showed that the motive of disease avoidance rivals the motive of affiliation in shaping people's experiences of social interactions. These findings suggest that cues of disease salience alter people's affective experience with inclusion but not exclusion. The current research represents an important step toward understanding people's affective responses to social exclusion and inclusion in complex social situations involving multiple, and potentially conflicting motives. (PsycInfo Database Record (c) 2023 APA, all rights reserved).