Objective The aim was to examine whether trait positive and negative affect (PA, NA) moderate the stress‐buffering effect of perceived social support on risk for developing a cold subsequent to being exposed to a virus that causes mild upper respiratory illness. Method Analyses were based on archival data from 694 healthy adults (Mage = 31.0 years, SD = 10.7 years; 49.0% female; 64.6% Caucasian). Perceived social support and perceived stress were assessed by self‐report questionnaire and trait affect by aggregating responses to daily mood items administered by telephone interview across several days. Subsequently, participants were exposed to a virus that causes the common cold and monitored for 5 days for clinical illness (infection + objective signs of illness). Results Two 3‐way interactions emerged—Support × Stress × PA and Support × Stress × NA. The nature of these effects was such that among persons with high trait PA or low trait NA, greater social support attenuated the risk of developing a cold when under high but not low perceived stress; this stress‐buffering effect did not emerge among persons with low trait PA or high trait NA. Conclusions Dispositional affect might be used to identify individuals who may be most responsive to social support and support‐based interventions.