Estimates suggest that 25–50% of family caregivers experience depression. Recent research has linked psychological stress and depression symptoms to increased cytokine activity. This study was designed to investigate the predictors of high cytokine levels and their influence with personality factors on depression in a caregiving population. The authors examined the relationship between caregiving burden and depression through the influence of sociotropy, autonomy, and cytokine levels in a sample of 106 caregivers who were actively caring for an elderly dependent in the community. Though the authors did not establish a mediation model, they found that the personality sub-factors of sociotropy, predicted tumor necrosis factor receptor (TNFR1) levels, while burden significantly predicted interleukin-6 and C-reactive protein (CRP) levels. Additionally, burden and TNFR1 levels predicted depression, with greater burden and TNFR1 levels predicting increased depression severity. Study findings point to a need for early interventions for caregivers to prevent increases in stress and cytokine levels and the development of depression.