Description: Objective In 2008, the Thai government introduced the ‘high-cost medicines E2 access program’ as a part of the National List of Essential Medicines to increase patient access to medicines, improve clinical outcomes and make medicines more affordable. Our objective was to examine whether the ‘high-cost medicines E2 access program’ achieved its goals. Design Interrupted time-series design study. Setting 3 tertiary hospitals in different regions of Thailand, January 2006 to December 2012. Participants Patients with target acute and chronic disease diagnoses who newly met E2 program criteria for selected study medicines. Intervention High-cost medicines E2 access program. Main outcomes measures Level and trend changes over time in the proportions of eligible patients who received the indicated E2 medicines and who improved clinically, as well as in costs of treatment. Results A total of 2024 patients were included in utilisation analyses and 1375 patients with selected acute diseases contributed to analyses of clinical outcome. After 1 year of the E2 program implementation, the percentage of eligible patients receiving the indicated E2 program medicines increased significantly (relative change 12.7% (95% CI 4.4% to 21.0%), especially among those insured by the government's universal coverage scheme (relative change 19.9% (95% CI 9.5% to 30.5%)). The increase in the proportion of clinically improved patients with acute conditions was not significant (relative change 6.2% (95% CI –1.9% to 15.1%)). Quarterly healthcare costs per patient dropped significantly (relative change –13.5% (95% CI –26.9% to –1.7%)). Conclusions In the study hospitals, the E2 access program seems to have facilitated patient access to specialty medicines, may have contributed to improved health outcomes, and decreased treatment costs. Routine monitoring is needed to assess effects of expanding the programme, including effects on quality of care and financial sustainability.