This project explores how children disambiguate and retain novel object-label mappings in the face of semantic similarity. Burgeoning evidence suggests that semantic structure in the developing lexicon promotes word learning in ostensive contexts, whereas other findings indicate that semantic similarity interferes with and temporarily slows familiar word recognition. This project explores how these distinct processes interact when mapping and retaining labels for novel objects (i.e., low-frequency objects that are unfamiliar to toddlers) via disambiguation from a semantically similar familiar referent in 24-month-olds (N = 65). Toddlers’ log-adjusted looking to labeled target objects (relative to distractor objects) was measured in three conditions: Familiar trials (familiar label spoken while viewing semantically related familiar and novel objects), Disambiguation trials (unfamiliar label spoken while viewing semantically similar familiar and unfamiliar object), and Retention trials (unfamiliar label spoken while viewing novel object pairs). Toddlers’ individual vocabulary structure was then compared to performance on each condition. Vocabulary structure was measured at two levels: category-level structure (semantic density) for experimental items, and lexicon-level structure (global clustering coefficient). The findings suggest, consistent with prior results, that semantic density interfered with known word recognition, and facilitated unfamiliar word retention. Children did not show a significant novel word preference during disambiguation, and disambiguation behavior was not impacted by semantic structure. These findings connect seemingly disparate mechanisms of semantic interference in processing and semantic leveraging in word learning. Semantic interference momentarily slows word recognition and resolution of referential uncertainty for novel label-object mappings. Nevertheless, this slowing might support retention by enabling comparison between related objects.