Introduction: Acute heart failure (AHF) involves a rapid decline in cardiac pumpfunction, leading to congestion, dyspnea, and a high risk of readmission and mortality.Renal impairment is common, and diuretic resistance complicates fluid removal. Againstthis background, rolofylline — a selective adenosine A1 receptor antagonist — wasevaluated for its potential to improve natriuresis and diuresis.Aim: To critically assess the clinical efficacy and safety data—primarily from thePROTECT trial—that formed the basis for the decision to withdraw rolofylline from themarket in September 2009, with a focus on understanding the lack of clinical benefit andthe emergence of serious adverse events.Methods: A systematic PubMed search was conducted in September 2025. Ofapproximately 1,660 records, 18 publications remained after filtering. Five randomizedclinical studies were included: three Phase II trials evaluating the hemodynamic and renaleffects of rolofylline, the large Phase III PROTECT trial, and a complementary secondaryanalysis focusing on neurological safety outcomes and post-discharge prognosis.Results: Rolofylline increased urine output early and thereby reduced the need forintravenous furosemide. Creatinine improved at intermediate doses, but signs of increasedrisk for serious adverse events appeared at the highest dose. In the large PROTECT trial,no improvement was observed in sustained renal impairment or composite clinicaloutcomes compared with placebo, despite slightly greater weight loss; seizures were morefrequent. Hemodynamically, lower filling pressures and a slightly higher cardiac indexwere noted, but without lasting symptomatic or renal benefits. Post-discharge riskremained high, with urea, sodium, and albumin levels showing significant associationswith these outcomes.Conclusion: Rolofylline produces short-term increases in diuresis but does not improverenal function or hard clinical outcomes. The increased risk of neurological adverseevents, particularly seizures, persists. Given the limited clinical benefit and remainingsafety concerns, future focus should be directed toward developing individualizeddecongestion strategies and risk stratification.