The effect of boiling and natural fermentation on Qulle and Kello cassava varieties collected from southern Ethiopia were studied for their physicochemical composition and antinutritional factors. The moisture content of the samples was 9.47±0.47% for Qulle variety and 8.48±0.02% for Kello variety for raw samples. Based on dry weight basis, the ash, fat, protein, crude fibre and total carbohydrate were 3.45±0.20, 0.88±0.10, 1.32±0.06, 3.44±0.00, and 90.55±0.19 % respectively for the raw sample of Qulle variety and 2.43±0.13, 1.02±0.10, 1.47±0.02, 2.82±0.14, 91.76±0.84 % for the raw sample of Kello variety. The energy values are 376.86±1.28 and 386.55±1.93 Kcal/100g for the samples of Qulle and Kello variety respectively. Among the antinutritional factors analyzed, the level of cyanide, phytate, tannin and oxalate were determined to be 4.62±0.01, 543.97±0.74, 1.70±0.33 and 24.93±0.08 mg/100g in raw Qulle sample respectively and 5.04±0.02, 168.24±5.53, 1.82±0.03 and 86.18±0.10 mg/100g in raw Kello sample respectively. Significant difference (p