The languages of the world differ in their use of intrinsic, relative, and absolute reference frames to describe spatial relationships, but factors guiding reference frame choices are not yet well understood. This paper addresses the role of animacy and linguistic construction in reference frame choice in English and Spanish. During each trial of two experiments, adult participants saw a spatial scene along with a sentence describing the location of an object (locatum) relative to another object (relatum) that was animate or human(-like) to varying degrees. The scene presented two possible referents for the locatum, and participants decided which referent the description referred to, revealing which reference frame they used to interpret the sentence. Results showed that reference frame choices differed systematically between languages. In English, the non-possessive construction (X is to the left of Y) was consistently associated with the relative reference frame, and the possessive construction (X is on Y’s left) was associated with the intrinsic reference frame. In Spanish, the intrinsic interpretation was dominant throughout, except for the non-possessive construction with relata that were not anthropomorphic, animate, or human. We discuss the results with respect to the languages’ syntactic repertory, and the notion of inalienable possession.