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Tablet splitting is a method of dividing a tablet into smaller pieces to obtain a recommended dosage according to a client's individual needs. Almost exclusively, oral tablets are dispensed in the prescription strengths most frequently given to patients. Sometimes, the required amount may not be available in the pharmacy, so one and a half pills or just half a pill might be needed. Tablet splitting is an extemporaneous compounding practice performed by pharmacists or nurses in the clinical setting. However, there is limited peer-reviewed research on the actual variations in splitting methods of tablet splitting in Ethiopia. Therefore, this study aimed to compare the effect of tablet splitting methods on mass loss and weight uniformity of tablets split by hand and tablet splitter methods. Whole tablets were randomly selected from each medication lot for each of the five products and weighed individually using a sensitive analytical balance; the average weight loss per tablet type was calculated. Four nurses were randomly selected to perform the splitting process. The weight variation and loss between the two splitting methods were compared using Microsoft Excel and SPSS version 25 for direct descriptive statistical analysis in accordance with FDA-referenced and USP General Chapter [Formula: see text] - Quality Attributes of Tablets Labeled as Having a Functional Score referenced thresholds descriptive benchmarks. The weight loss of five individual drugs during splitting was evaluated, and only 60% of the hand splits and 20% of the cutter splits satisfied the FDA acceptance criteria (weight loss less than 3%). According to the USP General Chapter [Formula: see text] and USP weight uniformity test descriptive benchmark, 60% of the study tablet products subjected to splitting by hand yielded half tablets and exceeded the FDA-referenced benchmark used for descriptive comparison (% (RSD less than 6). Among those tablets exposed to splitter splitting, 80% showed lower weight uniformity test (% RSD (less than 6%). This finding also showed that, of all five sampled tablet medications, those split by the splitter showed height and weight variation compared with those split by hand. According to FDA and USP General Chapter [Formula: see text]-Quality Attributes of Tablets Labeled as Having a Functional Score referenced thresholds and descriptive benchmarks, both methods were subjected to mass loss and weight variability, where hand splitting showed lower mass loss and less variability than tablet splitters.