Background: Interoperability-the exchange and integration of data across the health care system-remains a challenge despite ongoing policy efforts aimed at promoting interoperability.

Objective: This study aimed to identify current challenges and opportunities to advancing interoperability across stakeholders.

Methods: Primary data were collected through qualitative, semistructured interviews with stakeholders (n=24) in Ohio from July to October 2021. Interviewees were sampled using a stratified purposive sample of key informants from 4 representative groups as follows: acute care and children's hospital leaders, primary care providers, behavioral health providers, and regional health information exchange networks. Interviews focused on key informant perspectives on electronic health record implementation, the alignment of public policy with organizational strategy, interoperability implementation challenges, and opportunities for health information technology. The interviews were transcribed verbatim followed by rigorous qualitative analysis using directed content analysis.

Results: The findings illuminate themes related to challenges and opportunities for interoperability that align with technological (ie, implementation challenges, mismatches in interoperability capabilities across stakeholders, and opportunities to leverage new technology and integrate social determinants of health data), organizational (ie, facilitators of interoperability and strategic alignment of participation in value-based payment programs with interoperability), and environmental (ie, policy) domains.

Conclusions: Interoperability, although technically feasible for most providers, remains challenging for technological, organizational, and environmental reasons. Our findings suggest that the incorporation of end user considerations into health information technology development, implementation, policy, and standard deployment may support interoperability advancement.