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Abstract Localizing macromolecules in crowded cellular cryo-electron tomography (cryo-ET) images or tomograms is crucial for determining their in situ structures. Traditional template matching-based approaches for this task suffer from template-specific biases and have low throughput. Given these problems, learning-based solutions are necessary. However, the paucity of annotated data for training poses substantial challenges for such learning-based methods. Moreover, preparing extensively annotated cellular tomograms for training macromolecule localization methods is extremely time-consuming and burdensome due to the large volume and low signal-to-noise ratio of the tomograms. In this work, we developed TomoPicker, an annotation-efficient macromolecule localization method for tomograms. To achieve such annotation-efficiency, TomoPicker regards macromolecule localization as a voxel classification problem and solves it with two different positive-unlabeled learning approaches. We evaluated TomoPicker on two experimental cryo-ET datasets of crowded eukaryotic cells and one experimental dataset of relatively less crowded prokaryotic cell. We observed that, with only 10 annotated macromolecule locations, TomoPicker with positive unlabeled learning achieved a performance comparable to that of state-of-the-art supervised methods trained with several hundred annotations. In other words, TomoPicker achieved plausible segmentation with up to 98% less data compared with supervised learning-based methods. Furthermore, it demonstrated substantial improvements over existing learning-based macromolecule localization methods under sparse annotation scenarios.