Background: Adult T-cell leukemia (ATL) is one of the most important hematological malignancies caused by the HTLV-I virus. The disease has a poor prognosis due to the low median survival of the patients. Aim: Given the need for effective therapeutic interventions, this study aimed to investigate the efficacy of Hyper-CVAD and As/IFN/AZT regimens and compare their performance. Methods and Results: This study is a randomized clinical trial conducted on individuals recently diagnosed with acute ATL. Individuals who tested positive in a HTLV-I serological test based on ELISA and/or PCR were randomly assigned to receive treatment with either Hyper-CVAD or As/IFN/AZT using block randomization. The drug regimens were administered for 60 days, and patients underwent follow-up assessments. Overall, 29 individuals were enrolled in the trial. No significant differences were found in gender distribution, LDH levels, and lymphocyte counts between the two groups (P-value>0.05). The treatment response rates for the Hyper-CVAD and As/IFN/AZT regimens were 46.67% and 35.71%, respectively, with no significant differences between the two groups (P-value >0.05). Survival analysis revealed a significant difference in survival between the two groups, favoring those under the Hyper-CVAD regimen (P-value<0.05). The predominant toxicities were hematological toxicities; one patient in the Hyper-CVAD group experienced Grade 3 toxicity, while three patients in the As/IFN/AZT group experienced Grade 3 toxicity. Conclusion: The results of this study suggest no significant differences in efficacy between the Hyper-CVAD and As/IFN/AZT regimens. Additionally, higher toxicity rates were observed in the As/IFN/AZT regimen. Further investigations into frontline treatments and the timing of the As/IFN/AZT regimen in future studies may provide valuable insights in this regard. Clinical Trial Registration: IRCT20210703051770N1.