HiChIP is a novel protein-centric chromatin conformation method that significantly improves the yield of conformation-informative reads and reduces input requirements compared to ChIA-PET. By leveraging in situ Hi-C and transposase-mediated on-bead library construction, HiChIP enhances the specificity and efficiency of chromatin interaction mapping. The method was validated using cohesin subunit Smc1a in human B lymphocytes and mouse embryonic stem cells, demonstrating higher efficiency and signal-to-background ratio compared to ChIA-PET. HiChIP also showed robust reproducibility and comparable loop calls to in situ Hi-C, even at lower cell numbers. The ability to sustain high-confidence contact maps at low cell numbers makes HiChIP a valuable tool for studying chromatin conformation in diverse biomedical applications.HiChIP is a novel protein-centric chromatin conformation method that significantly improves the yield of conformation-informative reads and reduces input requirements compared to ChIA-PET. By leveraging in situ Hi-C and transposase-mediated on-bead library construction, HiChIP enhances the specificity and efficiency of chromatin interaction mapping. The method was validated using cohesin subunit Smc1a in human B lymphocytes and mouse embryonic stem cells, demonstrating higher efficiency and signal-to-background ratio compared to ChIA-PET. HiChIP also showed robust reproducibility and comparable loop calls to in situ Hi-C, even at lower cell numbers. The ability to sustain high-confidence contact maps at low cell numbers makes HiChIP a valuable tool for studying chromatin conformation in diverse biomedical applications.