Preliminary evidence shows that ethyl-eicosapentaenoate (E-EPA) has a marked clinical effect when used as an adjunct in therapy-refractory depression. EPA belongs to the class of polyunsaturated omega-3 fatty acids. The mechanism of its action in depression is not fully understood. There are two related fields where the pathophysiology of refractory depression meets the effect of EPA. First, a general immunosuppressive effect of EPA meets a general immunoactivation in severe depression, especially an increase in CD4/CD8 ratio, neutrophilia, and an increase in interleukins (IL)-6 and IL-12 and of prostaglandin E2 (PGE2). Secondly, a resistance to dexamethasone (Dex) suppression of the HPA axis meets the effects of EPA on multidrug resistance reversing and HPA axis suppression. The effects of EPA on the immune system, the HPA axis, and multidrug resistance are connected through the action of a transport protein called p-glycoprotein (p-gp). Physiological and synthetic steroids such as cortisol and Dex are substrates of p-gp, and so Dex resistance in depression may be related to dysfunction of this protein. In addition, expression of p-gp is induced by PGE2, and EPA inhibits the synthesis of PGE2. The reversal of drug resistance by EPA may be mediated via this immunological mechanism and lead to its antidepressive efficacy. In addition, antidepressants such as amitriptyline, which have special efficacy in severe depression, decrease p-gp function. EPA may, furthermore, enhance the action of antidepressants, like many SSRIs that are p-gp substrates, which are actively transported out of the intracerebral space at the level of the blood-brain barrier.