Background: A significant portion of adults struggle to read at a basic level. Word reading (defined here as decoding and word recognition) appears to play a pivotal role for this population of readers; however, less is known about how word reading relates to other important semantic processes (e.g., vocabulary, sentence processing) known to account for a large portion of variance in reading comprehension. This study used the Reading Systems Framework to explore the extent that moderational and mediational relations existed between word reading and semantic processing abilities in predicting reading comprehension. Methods: Participants (N = 169) completed the Reading Inventory and Scholastic Evaluation, which consists of a series of subtests intended to measure decoding/word recognition, vocabulary, sentence processing and reading comprehension.Results: A moderated mediation model was constructed to assess the extent to which moderational and mediational relations between word reading and semantic processing were predictive of comprehension. Results suggested that word reading moderated the effect of vocabulary knowledge on comprehension among struggling adult readers. Additionally, semantic processing at the word (i.e., vocabulary) and sentence level both significantly mediated the relation between word reading and comprehension.