A nonrandomized controlled study was conducted to evaluate the effect of lipo-prostaglandin E1 (lipo-PGE1) on cystatin C (CysC), β2-microglobulin (B2MG), and estimated glomerular filtration rate (eGFR) in patients with decompensated heart failure (DHF) and renal dysfunction. A total of 286 enrolled patients with DHF and renal dysfunction were nonrandomly assigned a 7-day standard treatment without (n = 146) or with (n = 140) lipo-PGE1 intervention. According to the baseline eGFR, patients were further classified into mild, moderate, and severe renal dysfunction subgroups. By the end of study period, there was no evidence of an immense improvement in B2MG, CysC, and eGFR in response to standard treatment (all P > 0.05). On the contrary, a noticeable decrease of B2MG and CysC was observed in patients receiving lipo-PGE1 intervention, as well as an increase in eGFR (all P < 0.05). Moreover, lipo-PGE1 intervention led to greater changes in renal function variables from baseline than with standard management (all P < 0.05). Most important, the favorable renal protective effects of lipo-PGE1 were maintained in three subgroups. Lipo-PGE1 intervention brought a substantial renoprotective benefit to hospitalized DHF patients as compared with standard therapy, suggesting it might offer a promising therapeutic option for the management of renal dysfunction associated with DHF.