Plasma volume fluctuations limit the utility of circulating lipidomics in chronic heart failure (CHF). In contrast, red blood cell (RBC) membrane lipidomics may serve as stable biomarkers that are unaffected by plasma volume changes. Two cohorts are included to investigate the association between RBC indicators and CHF. RBC membrane lipidomics is first used to characterize CHF and its impact on plasma volume overload (PVO) and major adverse cardiovascular events (MACE). The first cohort (n = 507,638) shows that the erythrocyte stress index (ESI), better than traditional RBC indicators, is associated with the prevalence of CHF with odds ratio (OR) and confidence interval (CI) of 1.57 (95% CI,1.55-1.59). ESI is also linked with in-hospital death in CHF. Another cohort (n = 1,550) indicated RBC membrane lipidomics ceramide subtype Cer 18:0;O2/16:0 and lysophosphatidylethanolamine subtype LPE 18:0 has an AUC of PVO with 0.75 and 0.61. The above two lipids are risk factors of PVO with OR of 1.62 (95% CI, 1.47-1.80) and 1.11 (95% CI, 1.06-1.16). They also are risk factors for MACE, with hazard ratios (HR) of 1.04 (95% CI, 1.01-1.07) and 1.06 (95% CI, 1.01-1.10). This research emphasizes the potential value of RBC membrane lipidomics for CHF development, prognosis, and treatment.