Antecedent use of renin-angiotensin system inhibitors (RASi) prevents clinical deterioration and protects against cardiovascular/thrombotic complications of COVID-19, for indicated patients. Uncertainty exists regarding treatment continuation throughout infection and doing so with concomitant medications. Hence, the purpose of this study is to evaluate the differential effect of RASi continuation in patients hospitalized with COVID-19 according to diuretic use. We used the Coracle registry, which contains data of hospitalized patients with COVID-19 from 4 regions of Italy. We used Firth logistic regression for adult (>50 years) cases with admission on/after February 22, 2020, with a known discharge status as of April 1, 2020. There were 286 patients in this analysis; 100 patients (35.0%) continued RASi and 186 (65%) discontinued. There were 98 patients treated with a diuretic; 51 (52%) of those continued RASi. The in-hospital mortality rates in patients treated with a diuretic and continued versus discontinued RASi were 8% versus 26% (p = 0.0179). There were 188 patients not treated with a diuretic; 49 (26%) of those continued RASi. The in-hospital mortality rates in patients not treated with a diuretic and continued versus discontinued RASi were 16% versus 9% (p = 0.1827). After accounting for age, cardiovascular disease, and laboratory values, continuing RASi decreased the risk of mortality by approximately 77% (odds ratio 0.23, 95% confidence interval 0.06 to 0.95, p = 0.0419) for patients treated with diuretics, but did not alter the risk in patients treated with RASi alone. Continuing RASi in patients concomitantly treated with diuretics was associated with reduced in-hospital mortality.