Hyperiidea is an exclusively pelagic suborder of amphipod crustaceans, exhibiting a wide array of unique adaptations to life in the dark, open expanse of the oceanic midwater. No common morphological synapomorphy unites approximately 350 described species. Instead, hyperiid amphipods are defined only by their pelagic existence. Hyperiidea exhibits many of the characteristics of an adaptive radiation and could represent a midwater example of this phenomenon. Previous morphological and molecular analyses have led to uncertainty in the shared ancestry of Hyperiidea. The evolutionary history of their diverse adaptations, as well as their relationship to other amphipods, remains unknown. Here we present results of a multi-locus phylogenetic analysis of publicly available amphipod sequences for three nuclear loci (18S, 28S, and H3) and two mitochondrial loci (COI and 16S) from over 300 amphipod genera, 40 of which are hyperiids. We recover strong support for a monophyletic Hyperiidea as well as reciprocally monophyletic hyperiid infraorders Physocephalata and Physosomata (with enigmatic genera Cystisoma and Paraphronima more closely related to Physosomata). We also identify several benthic, commensal amphipods representing potential sister groups for Hyperiidea. These taxa have not previously been considered close hyperiid relatives and include the genera Amphilochus, Colomastix, Anamixis, Paranamixis, and Leucothoe. Our results support the current definition of Hyperiidea and inform the phylogenetic placement of the suborder within Amphipoda.