Background: Cardiopulmonary bypass (CPB) can adversely affect coagulation and systemic inflammatory response. Given that the optimal strategy for priming CPB in cardiac surgery remains a matter of debate, this study aimed to investigate the effects of albumin 20% and hydroxyethyl starch 6% as priming solutions on bleeding and interleukin-6 (IL-6) levels during CPB. Methods: This randomized clinical trial involved 40 patients undergoing coronary artery bypass surgery at Shahid Chamran Hospital between July 2021 and July 2022. Participants were assigned to 2 groups: the first group received 50 mL of albumin 20% as the priming solution for the CPB circuit, while the second group received 500 mL of hydroxyethyl starch 6%. Bleeding and IL-6 levels were assessed before and after the intervention. Results: The albumin group comprised 80.0% men and 20.0% women, with a mean age of 66.45±5.84 years. The hydroxyethyl starch 6% group consisted of 85.0% men and 15.0% women, with a mean age of 63.05±5.92 years (P>0.05). The findings revealed that 12 hours after CPB, the IL-6 level in the hydroxyethyl starch 6% group (mean: 171.6±77.71 pg/mL) was significantly higher than that in the albumin group (mean: 105.8±36.45 pg/mL; P=0.002). At 48 hours after CPB, the mean bleeding was not significantly different between the groups (P=0.950). Conclusion: Albumin 20% was more effective than hydroxyethyl starch 6% concerning IL-6 levels. However, no significant differences in bleeding were observed between the groups at 48 hours post-CPB.