A number of polychlorinated (phenoxyphenyl)acetic acids were prepared as close structural analogues of the antiinflammatory compound fenclofenac, [2-(2,4-dichlorophenoxy)phenyl]acetic acid. Increased potency was shown in several of these compounds, in particular, [2-(2,3,5,6-tetrachlorophenoxy) phenyl]acetic acid (8), which was 40 times more potent than fenclofenac in the adjuvant-induced arthritis screen. In further tests it was found to be equipotent with indomethacin but with a much reduced incidence of acute toxicity (LD50 and ulcerogenicity). On chronic dosing, however, serious toxicity problems arose (including anemia, neutrophilia, and severe peritonitis), and this led to the abandonment of further work on the compound. Three further analogues were prepared containing NH, S, and SO moieties bridging the phenyl rings. Although the NH compound bore a very close structural resemblance both to the above O-linked compound and the potent antiinflammatory drug diclofenac, [2-[(2,6-dichlorophenyl)imino]phenyl]acetic acid, it showed low activity in primary screens. Similarly, neither the S- or SO-bridged analogues had potencies that approached that of 8.