Simple SummaryProteinuria is a common adverse event of systemic therapy for hepatocellular carcinoma (HCC); however, its effect on clinical outcomes is not well understood. A retrospective analysis of 321 patients with unresectable HCC who received systemic therapy as first-line treatment was performed to assess the impact of pretreatment proteinuria on treatment response. Patients without pretreatment proteinuria who received lenvatinib or atezolizumab plus bevacizumab had longer overall survival, but those treated with sorafenib did not. Additionally, a quantitative analysis of 111 patients treated with lenvatinib or atezolizumab plus bevacizumab revealed that the severity of proteinuria was an independent predictor of prognosis, along with liver function. Therefore, pretreatment proteinuria may predict a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib.AbstractBackground: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. Method: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. Results: In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. Conclusion: Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib.