Background and Aims: Interleukin (IL)-6, IL-8, IL-10, and C-reactive protein (CRP) have been evaluated for predicting outcomes of acute pancreatitis. However, there is considerable variation in their performance among different studies. We evaluate their accuracy in predicting progression to severe pancreatitis. Materials and Methods: Serum IL-6, IL-8, IL-10, and CRP levels were measured within 24 h of admission in forty patients of clinically predicted severe acute pancreatitis (SAP). Persistent organ failure (>48 h) defined SAP. The performance of inflammatory markers was evaluated in predicting the progression of pancreatitis. Results: IL-6 ≥28.90 pg/mL had a sensitivity of 62.86%, specificity of 80%, positive predictive value (PPV) of 95.65%, LR+ of 3.1429, LR− of 0.4643, and diagnostic odds ratio (DOR) of 6.7692; IL-8 ≥88.70 pg/mL had a sensitivity of 60%, specificity of 80%, PPV of 95.45%, LR+ of 3.000, LR− of 0.5000, and DOR of 6.000; IL-10 ≤5.70 pg/mL had DOR of 0.2647, sensitivity of 51.43%, specificity of 20%, PPV of 81.82%, LR+ of 0.6429, and LR− of 2.4286. CRP ≥110.00 mg/L had DOR of 2.3636, sensitivity of 37.14%, specificity of 80%, PPV of 92.86%, LR+ of 1.8571, and LR of 0.7857. Conclusions: IL-6 ≥28.90 pg/mL, measured within 48 h of onset is the best among the tested biomarkers in this study for predicting the progression to severe pancreatitis.