Hydrocarbon depleted fractured shale (HDFS) formations could be attractive for geologic carbon dioxide (CO2) storage. Shale formations may be able to leverage existing infrastructure, have larger capacities, and be more secure than saline aquifers. We compared regional storage capacities and integrated CO2 capture, transport, and storage systems that use HDFS with those that use saline aquifers in a region of the United States with extensive shale development that overlies prospective saline aquifers. We estimated HDFS storage capacities with a production-based method and costs by adapting methods developed for saline aquifers and found that HDFS formations in this region might be able to store with less cost an estimated ∼14× more CO2 on average than saline aquifers at the same location. The potential for smaller Areas of Review and less investment in infrastructure accounted for up to 84% of the difference in estimated storage costs. We implemented an engineering-economic geospatial optimization model to determine and compare the viability of storage capacity for these two storage resources. Across the state-specific and regional scenarios we investigated, our results for this region suggest that integrated CCS systems using HDFS could be more centralized, require less pipelines, prioritize different routes for trunklines, and be 6.4–6.8% ($5-10/tCO2) cheaper than systems using saline aquifers. Overall, CO2 storage in HDFS could be technically and economically attractive and may lower barriers to large scale CO2 storage if they can be permitted.