The present study compared the effects of four lipophilic forms of selenium with regard to cancer chemopreventive activity, tissue selenium accumulation, and bioavailability for synthesis of a selenoprotein. These reagents included methylphenyl selenide, diphenyl selenide, triphenyl-selenonium chloride, and p-xylylbis(methylselenide). The maximum tolerable dose (added in the diet) for each of these compounds was 5, 30, > 200, and 5 ppm Se, respectively. Because of differences in their tolerance, the cancer chemopreventive activities (in a methylnitrosourea-induced mammary tumor model in rats) of all 4 compounds were assessed at the 5 ppm Se level. Methylphenyl selenide was the most effective--79% inhibition, followed by p-xylylbis-(methylselenide)--66% inhibition, triphenylselenonium chloride--27% inhibition, and diphenyl selenide--10% inhibition. With respect to tissue selenium levels, p-xylylbis(methylselenide) produced the highest accumulation of selenium (approximately 3-fold increase in liver and kidney, 14-fold increase in mammary gland); methylphenyl selenide and diphenyl selenide showed more modest increases (1.5-fold or less in liver and kidney, 2.5-fold or less in mammary gland); while triphenylselenonium chloride resulted in no change. Highest bioavailability of selenium was observed for p-xylylbis(methylselenide), which was followed closely by methylphenyl selenide. Bioavailability was very low with diphenyl selenide, and undetectable with triphenylselenonium chloride. The chemical reactivities of these different selenium compounds are discussed in relation to the biological effects reported here.