Background: Fibrosis in atrial myocardium is a common phenomenon for patients with atrial fibrillation (AF). Remodeling of connexins was found accompanying with AF. The aim of the study is to investigate whether it is by causing the remodeling of connexin 43 (Cx43) that the fibrosis of atrial muscle plays an important role during the initiation and maintenance of AF. Methods: Samples of right atrial appendage were taken from 24 patients with rheumatic valvular disease during surgery. Fibrosis and remodeling of Cx43 was examined by microscopy and ultramicroscopy technique and analyzed by image analyzer. The collagen volume fraction of type I (CVF-I) and the volume fraction of Cx43 (Cx43VF) were studied between AF and sinus rhythm (SR) groups. Results: (1) Microscopic examination demonstrated that CVF-I significantly increased and Cx43VF decreased in patients with AF compared to those with SR. (2) The CVF-I was negatively correlated with the Cx43VF. Conclusion: The results suggest that fibrosis and remodeling of Cx43 are involved in the pathophysiologic mechanism of human AF. Fibrosis of atrial muscle may play an important role in the process of AF by means of interfering with remodeling of connexins.