Objective To conduct a comparative analysis of the epidemic characteristics of hemorrhagic fever with renal syndrome (HFRS) in Northeast and Southwest China from 2005 to 2020, and to provide a reference for developing regional prevention and control strategies. Methods Descriptive epidemiological methods were used to analyze the epidemiological characteristics of HFRS outbreaks. The Joinpoint regression model was employed to calculate the annual percentage change (APC) and average annual percentage change (AAPC), thereby analyzing the trends in HFRS incidence. Results From 2005 to 2020, 63 878 HFRS cases were reported in Northeast China (average annual incidence: 3.58/100,000), showing a significant downward trend (AAPC=-13.08%, P<0.05). In Southwest China, 5 313 cases were reported (average annual incidence: 0.168/100 000) with stable overall incidence (AAPC=2.73%, P>0.05) but obvious inter-provincial differences. Northeast had a primary autumn-winter peak (Nov-Dec) and a secondary spring-summer peak (Apr-Jun), while Southwest showed the opposite seasonal pattern. For population distribution, both regions had males (Northeast: 45.01/100 000; Southwest: 1.76/100 000) and farmers aged 20-60 as the main high-risk groups, but differed in the second largest group: household workers/unemployed in the Northeast and students in the Southwest. Incidence presented an inverted ^”U^”-shape with age, peaking in the 40-50 years group. Geographically, high-incidence areas were widely distributed across multiple prefectures (e.g., Shuangyashan) in the Northeast, while in the Southwest, the distribution was highly concentrated, clustered only in a few ethnic minority autonomous prefectures such as Dali and Chuxiong in Yunnan. Conclusion The incidence of HFRS in Northeast China continues to decline, while it remains generally stable but shows localized increases in Southwest China, exhibiting regional differences in seasonal characteristics and geographical distribution. The differences in epidemic patterns across different regions may be related to climate and host species. Differentiated prevention and control strategies should be developed based on the specific epidemic characteristics of each region.