**Abstract** The neural mechanisms mediating the ability to make value-guided decisions have received substantial attention in both humans and animal models. Experiments in animals typically involve long training periods. By contrast, real-world decisions often need to be made spontaneously between novel options. It is therefore possible that neural mechanisms targeted in animal studies differ from those required for novel decisions typically revealed in human imaging studies. Here we show that primate medial frontal cortex (MFC) has a causal role in novel inferential choices when options have not previously been experienced. Macaques spontaneously inferred values of new options when their component parts had previously been encountered. Functional magnetic resonance imaging (fMRI) suggested this ability was mediated by MFC, an area rarely investigated in monkeys; MFC activity reflected a different process of comparison for novel versus familiar options. A second fMRI experiment found that multidimensional option representations in MFC employed a grid-cell-like coding scheme, well known in the context of spatial navigation, to integrate dimensions in this non-physical space when making novel choices. By contrast, orbitofrontal cortex held specific object-based value representations. In a third experiment, minimally invasive ultrasonic disruption of MFC, but not adjacent tissue, altered estimation of novel choice values.