Negative social experiences such as social stressors and isolation influence mental and physical illnesses, including affective disorders and heart disease. Studies focused on socially monogamous prairie voles can provide insight into neurobiological systems that underlie the consequences of negative social interactions. Female prairie voles were exposed to 28 days of social isolation or pairing with a female sibling (control). Voles were administered daily oxytocin [20 μg/50 μl, subcutaneous (sc)] or saline vehicle (50 μl, sc) for 14 days and exposed to two behavioral stressors [elevated plus maze (EPM) and resident-intruder test]. Brain tissue was collected for analysis of central peptide levels in the hypothalamic paraventricular nucleus (PVN). Isolation produced autonomic changes [increased heart rate (HR) and decreased HR variability) during both acute stressors and increased anxiety behaviors in the EPM. Oxytocin injection prevented the autonomic consequences of the acute stressors in isolated prairie voles, but did not affect the behaviors tested under the present conditions. Oxytocin had no effect on the behavioral or autonomic responsiveness in paired prairie voles. Oxytocin injection may exert a beneficial effect on autonomic responses to stressors in isolated animals through increasing the number of oxytocin-containing neurons and decreasing the number of corticotropin-releasing hormone-containing neurons in the PVN. Oxytocinergic mechanisms may serve to compensate for autonomic responses associated with chronic isolation and exposure to both social and non-social acute stressors.