To investigate the effect of additional Carbogen Nicotinamide (CON) to standard R-CHOP chemotherapy on HIF-1α and VEGF serum in DLBCL patients with tumor hypoxia. This is an interim analysis of an open-label clinical trial conducted at Dr. Kariadi Hospital Semarang. Newly diagnosed DLBCL patients with HIF-1α overexpression ≥10% were included and randomized into study group (R-CHOP plus nicotinamide and carbogen 10 liter/min) and control group (R-CHOP). From July-December 2021, 20 patients were enrolled and randomized. No significant differences in baseline clinical and laboratory parameters between both groups. Significant reductions were found in both HIF-1α (p=0.031) and VEGF (p=0.022) serum levels post-chemotherapy in the study group, however, no significant difference was found in the control group. CON (p=0.035; OR 9.3, 95%CI=1.2-72.9) and bulky tumor at presentation (p=0.012; OR 15.7, 95%CI=1.7-141.4) were significantly associated with the reduction of VEGF serum. The addition of CON in DLBCL patients could reduce the HIF-1α and VEGF serum levels significantly. Further studies are needed to confirm the positive effects of this intervention.