We have previously reported that compared to a corn oil diet a fish oil diet (5% by weight) fed to B10R.III mice before the induction of collagen induced arthritis markedly reduced disease severity. In this study we determine whether a fish oil diet could reduce the severity of collagen induced arthritis if begun after the arthritis was clinically apparent. Mice were initially fed either a fish oil or corn oil diet and immunized with bovine type II collagen 4 weeks later. At the onset of collagen-induced arthritis, half of the corn oil fed mice were switched to fish oil and arthritis assessed on a weekly basis. Four weeks after the diet change until killing 5 weeks later, the mice switched to fish oil developed much less severe arthritis than the corn oil fed controls. Thus the severity index of corn oil fed mice ranged between 9.4 and 7.1; the severity index of fish oil fed mice was between 6.8 and 4.3 while the mice switched to fish oil ranged between 7.2 and 5.6. Analysis of peritoneal macrophages 13 weeks after immunization showed that macrophages from fish oil fed mice incorporated eicosapentaenoic acid into phospholipids and produced less arachidonate products than corn oil fed mice. There was no difference between macrophages obtained from mice switched from corn oil to fish oil and those maintained on fish oil with respect to fatty acid composition of membrane phospholipids or prostaglandin profile. These results suggest that arthritis severity may be modulated after the onset of CIA by altering the PG profile of macrophages present at inflammatory sites.