<jats:title>Abstract</jats:title><jats:p>Three new iodinated tryptophan derivatives, plakohypaphorines D−F (<jats:bold>4</jats:bold>−<jats:bold>6</jats:bold>), have been isolated from the Caribbean sponge <jats:italic>Plakortis simplex</jats:italic>. Their structures have been determined by applying spectroscopic methods and microwave‐assisted selective dehalogenation. Compound <jats:bold>5</jats:bold> is the first naturally occurring triiodinated indole, while compound <jats:bold>6</jats:bold> is a unique metabolite because it possesses both chlorine and iodine atoms on the indole nucleus. We have evaluated the antihistamine activity of the whole series of plakohypaphorines A−F, but only the diiodinated analogues proved to be active: they display a specific antagonism of the noncompetitive type. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)