A sense of coherence (SOC) has been found to be a strong predictor of health outcomes and life satisfaction in older adults. This study investigated mood and immune effects of anticipated voluntary housing relocation in 30 healthy older adults and 28 age-matched controls and examined whether SOC would buffer effects of relocation on natural killer (NK) cell activity. Movers completed assessments and had blood drawn 1 month before relocation to congregate living facilities; controls were assessed concurrently. Compared with the control group, movers showed decreased positive mood and NK activity and elevated thought intrusion. Positive mood mediated the relationship of moving with NK activity, whereas SOC moderated this relationship. Low SOC movers had the poorest NK activity; that of high SOC movers was less compromised. These findings are consistent with possible salutogenic contributions of SOC and positive mood to immune function in older adults facing stressful life transitions.