Objective <p>Retroperitoneal fibrosis (RPF) is a rare condition marked by inflammation and fibrosis affecting the peritoneal and retroperitoneal soft tissues. In recent years, the identification of IgG4-related diseases has brought to light a significant association with fibrous disorders, including RPF, which were once considered independent. In this comprehensive cohort study, we performed a comparative analysis of the demographic, clinical, laboratory, histopathological, and therapeutic characteristics between patients with IgG4-related RPF and those with idiopathic retroperitoneal fibrosis (iRPF).</p> Methods <p>We performed a retrospective analysis of 117 patients diagnosed with RPF at the First Affiliated Hospital of Naval Medical University between July 2007 and July 2023.</p> Results <p>Demographic, clinical, laboratory, histopathological, and therapeutic characteristics of 70 iRPF patients and 47 IgG4-related patients were systematically compared. The IgG4-related group exhibited an older age of onset, with a predominant occurrence among adult males. Significantly elevated levels of eosinophilia and IgE were observed in the IgG4-related group. Most patients across both groups displayed elevated CRP and ESR levels. Furthermore, at the time of diagnosis, the IgG4-related group had higher serum creatinine and lower levels of complement. The most prevalent clinical manifestation in both groups was flank pain. The proportion of lymphoplasmic infiltration and storiform fibrosis in IgG4-related RPF group was significantly higher. The IgG4-related RPF group had significantly higher IgG4-positive plasma cell count, IgG4/total IgG ratio, and eosinophils count than that in iRPF group.</p> Conclusion <p>We conducted a comparative analysis of demographic, clinical, laboratory, histopathological, and therapeutic differences between the iRPF patients and the IgG4-related patients. Clarifying the distinctive characteristics of these two groups will contribute to a better understanding of the condition and facilitate the development of specific treatment strategies tailored to each group.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p><b>Key Points</b></p> <p>• <i>Identification of distinct clinical features and outcomes between IgG4-related and iRPF patients in a large retrospective study.</i></p> </entry> </row> </tbody> </tgroup> </Table></p>