Backgrounds: The absence of a gold-standard treatment for COVID-19 infection encourages clinicians to benefit from multipotential medications in the treatment of COVID-19. The current controlled randomized clinical trial tried to evaluate the efficacy and safety of pentoxifylline (PTX) as an adjuvant therapy in moderate to severe COVID-19 infection. Methods: In this randomized controlled clinical trial, two groups of hospitalized patients with moderate to severe COVID-19 infection were randomized by the block randomization method to either receive standard protocol therapy or standard protocol therapy plus pentoxifylline 400 mg TDS for 14 days. Results: The results showed a greater improvement in the proinflammatory biomarkers in the intervention group. Oxygen saturation, hemoglobin, and platelet levels were also improved to a higher level among pentoxifylline recipients. The mortality rate was reported 4% and 32% in the intervention and control groups, respectively. One out 13 patients with severe COVID-19 infection expired in the intervention group, while 20 out of 28 patients expired in the control group, showing about 10 times higher mortality rate compared to the pentoxifylline recipients. Conclusion: Pentoxifylline increased the survival rate of COVID-19 patients and played as a preventive role for COVID-related mortality and morbidity such as acute respiratory distress syndrome.