Background <p>ST-elevation myocardial infarction (STEMI) is a life-threatening and time-critical heart disease, and achieving equality in its management remains a major challenge. Rural-urban inequality has been previously identified as major driver of health inequality in STEMI management. How to effectively eliminate the rural-urban inequality of STEMI care remains a huge challenge.</p> Method <p>The study aims to evaluate the impact of the regional Network on rural-urban inequality of STEMI care in study setting. A new prefecture-wide STEMI Network was implemented in Chuxiong, an underdeveloped area of Southwest China. A longitudinal study including 5-years STEMI patients from real world and covering the three Network phases (Pre-network, Creation and Post-network phases) was conducted. Outcomes included various intervals of ischemic time, length of hospital stay and in-hospital charge. The total effects of the Network on STEMI care continuous outcomes were estimated using interaction Cox regression models.</p> Results <p>A total of 1436 patients were included in the study (285 rural and 95 urban cases during pre-network phase, 209 rural and 166 urban cases during creation phase, 397 rural and 284 urban cases during the post-network phase). After conditioning, significant reduction of rural-urban difference were found after network implementation: the rural-urban differences of patient delay with HR 1.00 [0.86, 1.17] in post-network phase compared with HR 0.50 [0.40, 0.64] in pre-network phase was no longer evident after the network; the rural-urban differences of total ischemic time with HR 0.92 [0.76, 1.11] in post-network phase compared with HR 0.45 [0.33, 0.61] in pre-network phase was no longer evident after the network. Following the network, narrowed rural-urban difference were found in system delay and reperfusion delay, but widened rural-urban difference were found in hospital stays.</p> Conclusions <p>The effectiveness of regional Network on reduction health inequality in STEMI care was evident in an under-developed area. It is suggested that the regional STEMI network could focus on promoting reperfusion by fibrinolysis not only in rural area but also in sub-urban area.</p> Trial registration <p>The study has been registered in Chinese Clinical Trial Registry (ChiCTR1900026935||<a href="http://www.chictr.org.cn/">http://www.chictr.org.cn/</a>) on October 26, 2019.</p>