HiChIP is a protein-centric method for analyzing genome architecture that improves the yield of conformation-informative reads by over 10-fold and reduces input requirements by 100-fold compared to ChIA-PET. HiChIP reveals multi-scale genome architecture with greater signal-to-background ratio than in situ Hi-C. The method leverages principles of in situ Hi-C and transposase-mediated on-bead library construction. HiChIP first establishes long-range DNA contacts in situ, then performs ChIP to capture long-range interactions associated with a protein of interest. Paired-end sequencing identifies two distantly located segments of the genome from one fragment, indicating the factor's association with the long-range interaction. HiChIP is robust, reproducible, and can be completed in as few as two days. HiChIP was validated using Smc1a in human B lymphocytes and mouse embryonic stem cells, showing higher efficiency and confidence in contact calling compared to ChIA-PET. HiChIP identified 27,697 ChIP peaks, with 79% overlapping with ENCODE Smc3 ChIP peaks. HiChIP also showed high confidence in identifying loops, with 81% of loops anchored by cohesin and 80% by CTCF, consistent with in-situ Hi-C data. HiChIP demonstrated robustness with low cell numbers, providing comparable results to ChIA-PET with 100-fold more starting material. HiChIP also showed higher signal-to-background ratio compared to in situ Hi-C, with increased signal at loop anchors and within loops. HiChIP was applied to Oct4 in mouse embryonic stem cells, showing Oct4 loops largely observed in the Smc1a dataset. HiChIP also showed potential for background signal reduction through normalization. HiChIP provides a rapid, efficient, and technically simplified way to assay protein-centric chromatin conformation. By enriching for cohesin, HiChIP offers an efficient alternative to deeply sequenced in situ Hi-C. The ability to sustain high confidence contact maps at low cell numbers will facilitate the investigation of chromatin conformation in systems previously unmeasurable by conventional strategies. HiChIP data is available in the NCBI Gene Expression Omnibus under accession number GSE80820.HiChIP is a protein-centric method for analyzing genome architecture that improves the yield of conformation-informative reads by over 10-fold and reduces input requirements by 100-fold compared to ChIA-PET. HiChIP reveals multi-scale genome architecture with greater signal-to-background ratio than in situ Hi-C. The method leverages principles of in situ Hi-C and transposase-mediated on-bead library construction. HiChIP first establishes long-range DNA contacts in situ, then performs ChIP to capture long-range interactions associated with a protein of interest. Paired-end sequencing identifies two distantly located segments of the genome from one fragment, indicating the factor's association with the long-range interaction. HiChIP is robust, reproducible, and can be completed in as few as two days. HiChIP was validated using Smc1a in human B lymphocytes and mouse embryonic stem cells, showing higher efficiency and confidence in contact calling compared to ChIA-PET. HiChIP identified 27,697 ChIP peaks, with 79% overlapping with ENCODE Smc3 ChIP peaks. HiChIP also showed high confidence in identifying loops, with 81% of loops anchored by cohesin and 80% by CTCF, consistent with in-situ Hi-C data. HiChIP demonstrated robustness with low cell numbers, providing comparable results to ChIA-PET with 100-fold more starting material. HiChIP also showed higher signal-to-background ratio compared to in situ Hi-C, with increased signal at loop anchors and within loops. HiChIP was applied to Oct4 in mouse embryonic stem cells, showing Oct4 loops largely observed in the Smc1a dataset. HiChIP also showed potential for background signal reduction through normalization. HiChIP provides a rapid, efficient, and technically simplified way to assay protein-centric chromatin conformation. By enriching for cohesin, HiChIP offers an efficient alternative to deeply sequenced in situ Hi-C. The ability to sustain high confidence contact maps at low cell numbers will facilitate the investigation of chromatin conformation in systems previously unmeasurable by conventional strategies. HiChIP data is available in the NCBI Gene Expression Omnibus under accession number GSE80820.