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Background The Tablo® Hemodialysis System (Tablo) is an all in one, easy-to-learn device featuring integrated water purification, on demand dialysate production and two-way wireless data transmission and is approved for use in the acute, chronic, and home settings. Prior reports have demonstrated Tablo’s ability to achieve clinical goals, seamlessly integrate into hospitals and reduce cost across a wide range of treatment times. Extension of the Tablo cartridge to 24 h allows prolonged therapy and even greater flexibility for prescribers in the acute setting. The objective is to report on the first ever experience with Tablo prolonged therapy between 12 and 24 h in critically ill patients treated at a single-center ICU. Methods Nursing staff were trained during a single training session on Tablo prolonged therapy. After a run-in period of five treatments, Tablo data were collected via real-time transmission to a cloud-based, HIPAA compliant platform and reviewed by site staff. Dialysis treatment delivery, clinically significant alarms, and clotting events were recorded. Sub-group analysis between COVID-19 positive and negative patients were reported. Results One hundred (100) consecutive Tablo prolonged treatments had a median prescribed treatment time of 24 h and a median achieved treatment time of 21.3 h. Median cartridge usage was 1.3 per treatment. The dialysis treatment time was delivered in 91% of treatments, with 6% ending early due to an alarm, and 3% ending due to clotting. Clinically significant alarms occurred at a median rate of 0.5 per treatment hour with a resolution time of 18 s. Median blood pump stoppage time related to these alarms was 2.3 min per treatment. Blood pump stoppage time was higher in the COVID-19 subgroup when compared to the non-COVID-19 subgroup. Conclusion Tablo successfully achieves prescribed treatment time with minimal therapy interruptions from alarms or cartridge changes. This data demonstrates the effectiveness of Tablo in achieving personalization of treatments necessary for unstable patients and enabling successful delivery of extended therapy with minimal clotting. Tablo’s prolonged therapy meets the needs of critically patients, including COVID-19 positive patients, requiring renal replacement therapy for greater than 12 h.