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 (M(age) = 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 x Stress x PA and Support x Stress x 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.