The perioperative period holds disproportionate impact on long-term cancer outcomes. Nevertheless, perioperative interventions to improve long-term cancer outcomes are not clinical routines, including perioperative stress-reducing or immune-stimulating approaches. Here, mimicking the clinical setting of pre-operative distress, followed by surgery, we examined the separate and combined effects of these events on the efficacy of pre-operative immune stimulation in rats and mice, and on post-operative resistance to tumor metastasis of the syngeneic mammary adenocarcinoma MADB106 in F344 rats and the CT26 colon carcinoma in Balb/C mice. The novel immune stimulating agents, GLA-SE or CpG-C (TLR-4 and TLR-9 agonists, respectively), were employed pre-operatively. Sixteen hours of pre-operative behavioral stressors (i) lowered CpG-C induced plasma IL-12 levels, and reduced resistance to MADB106 and CT-26 experimental metastases, and (ii) worsened the deleterious effects of laparotomy on metastasis in both tumor models. In rats, these effects of pre-operative stress were further studied and successfully abolished by the glucocorticoid receptor antagonist RU-486. Additionally, in vitro studies indicated the dampening effect of corticosterone on immune stimulation. Last, we tested a perioperative integrated intervention in the context of pre-operative stress and laparotomy, based on (i) antagonizing the impact of glucocorticoids before surgery, (ii) activating anti-metastatic immunity perioperatively, and (iii) blocking excessive operative and post-operative adrenergic and prostanoid responses. This integrated intervention successfully and completely abolished the deleterious effects of stress and of surgery on post-operative resistance to experimental metastasis. Such and similar integrated approaches can be studied clinically in cancer patients.