Benzoxazoles are DNA base bioisosteres and studies suggest that their derivatives have antiproliferative activities. Based on their antiproliferative activities they have been mostly studied as new generation anticancer drugs. In our study we exploited their antiproliferative effect, aiming to delineate bisbenzoxazole derivatives’ (RHE 231 and RHE 238) potential antiinflammatory effect on mouse macrophages that are activated in vitro through danger signal LPS stimulation. RAW 267.4 mammalian macrophages were activated in the presence of our derivatives with or without danger mimic E. coli derived LPS. We present data that support the strong antiinflammatory activity of the bisbenzoxazole derivatives RHE 231 and RHE 238 on stimulated mammalian macrophages. There was a significant and substantial decrease in the production levels of TNF- , IL-1 , and IL-6 proinflammatory cytokines in the presence of RHE 231 and RHE 238. These molecules had an antiproliferative effect on the macrophages and, probably, this was their mechanism of action on the cells to alter their inflammatory functions. Our results show that bisbenzoxazole structures RHE 231 and RHE 238 have potential to be used as antiinflammatory drug agents.