There is evidence that increased inflammatory activity contributes to treatment non-response in depression and studies suggest that omega-3 fatty acid supplementation is effective in antidepressant non-responders. We tested the hypotheses that in major depression (1) the plasma omega-6:omega-3 fatty acid ratio is greater in antidepressant non-responders than responders and (2) higher omega-6:omega-3 ratios are associated with a pro-inflammatory cytokine profile. Twenty DSM-IV major depressives who had failed a six week course of an SSRI, 14 subjects who responded to a six week course of an SSRI and were currently euthymic and 24 healthy comparison subjects took part in the study. Six millilitres of whole blood was collected in ethylenediaminetetraacetic acid (EDTA) tubes for determination of fatty acids together with IL-6 and TNF-alpha. Arachidonic acid (AA) levels were elevated in both the responders and the non-responders. IL-6 was elevated in a similar manner but differences in TNF-alpha did not reach statistical significance. The eicosapentaenoic acid (EPA):AA ratio in the three groups was as follows: controls 0.08+/-0.01; responders 0.08+/-0.01; non-responders 0.04+/-0.01. These differences are significant (p<0.001). AA and IL-6 were highly correlated in both responders and non-responders but not in healthy volunteers. The findings of this study provide further support for the view that major depression is associated with a pro-inflammatory phenotype which at least partially persists when patients become normothymic.