The relationship between the structure of aliphatic selena-carboxylic acids, CH 3(CH 2) m Se(CH 2) n COOH, and their potency in the prevention of dietary liver necrosis has been investigated in rats. Series of selena-carboxylic acids containing straight chains with equal numbers of carbon atoms on both sides of the selenium atom, selena-pentadecanoic and -hexadecanoic acids comprising all possible positions of the selenium atom in the carbon chain, selena-capramides, selena-undecanamides, 4-selena-carboxylic acid amides, and a series of 12-selena-carboxylic acids with 13 to 33 carbon atoms in the alkyl residue were studied. Several long chain selena-acids with methyl or hydroxyl substituents, selena-acids containing 2 or 3 selenium atoms at various positions, and some 2-carboxyl-13-selena-acids were also tested. The acid amides of many of the compounds were included. Four main regularities were detected in the relationship between structure and activity: (1) An alternating effect is exerted by the two carbon chains attached to the selenium atom. Even-numbered chains produce low, and uneven-numbered chains produce high, activity. The pattern is analogous to that found in selena-dicarboxylic acids (monoseleno-dicarboxylic acids). (2) If the selenium atom is located near the center of the molecule, high potencies are observed for compounds with uneven-numbered carbon chains on both sides of the selenium atom. (3) Alkyl residues with chain lengths C 3 and C 4 strongly depress activity. (4) The acid amides of selena-carboxylic acids are consistently more potent than the free acids, except for compounds containing more than one selenium atom in the chain. Rules 1 and 2 are explainable in terms of the topical relations between the selenium atom and the terminal carboxyl and methyl groups. In the extended, linear conformation, selenium atom and terminal groups are situated on the same side of the carbon chain when the number of carbon atoms in the chain is even, and on opposite sides when it is uneven. The bond angle of CH 2SeCH 2 bridge introduces a bend between the two moieties of the molecule. The end groups seem less accessible to binding in the even-numbered case because of the angle in the chain. The diminishing effect of C 3 and C 4 residues on biological potency (rule 3) could be due to interaction of the selenium atom with the terminal groups and formation of selenium containing 5- or 6-membered rings. The enhanced potency of acid amides (rule 4) may be related to differences in the lipid/water distribution coefficients.