I examined human–animal relationships (HARs) in zoo-housed orangutans (Pongo abelii) and gorillas (Gorilla gorilla gorilla) to see if they followed patterns similar to conspecific relationships in great apes and humans. Familiarity and social relationships guide humans' and great apes' behaviors with conspecifics. Inter-individual relationships, based on shared social history, and “generalized” relationships, based on a history of interactions with relevant classes of individuals, guide behavior with familiar and unfamiliar conspecifics, respectively. I examined whether both familiarity and social relationships similarly guides great apes' cross-species interactions with humans. I used repeated measures MANOVA to compare hourly rates and average durations of ape-initiated human-directed behaviors (HDBs) between familiar and unfamiliar humans and between great ape species. HDB patterns were consistent with familiarity-based HAR predictions, indicating more negative relationships with unfamiliar humans and more positive relationships with familiar humans. Findings for unfamiliar humans are consistent with negative effects of humans on apes' behavior reported in traditional visitor effect studies (VES). However, findings for familiar humans may be overlooked in VES due to pooling across levels of human familiarity or failure to consider humans other than primarily unfamiliar visitors. Additionally, species differences in apes' HDBs suggest that data pooling across species, common in many zoo studies, may mask important differences. These findings have important methodological implications for studies of human–animal interaction as well as for captive animal wellbeing. Am. J. Primatol. 76:942–955, 2014. © 2014 Wiley Periodicals, Inc.