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Peripheral T-cell lymphoma (PTCL) remains a formidable challenge in clinical management. Histone deacetylase inhibitor chidamide has demonstrated its anti-tumor effects in real-world studies in relapsed or refractory PTCL. To evaluate the efficacy of real-world utilization of chidamide combined with chemotherapy for untreated PTCL and explore relative prognostic factors, a cohort of 151 PTCL patients treated with chidamide combined with chemotherapy as front-line treatment in our center were enrolled. The overall response rate (ORR) and complete remission rate (CRR) at the end of treatment were 81.5% and 67.5%. The 7-year overall survival (OS) rate and progression-free survival (PFS) rate were 67.6% and 49.7%, with a median follow-up period of 21 months, showing its satisfactory efficacy and survival advantage. Most of adverse events were transient and reversible. Furthermore, several baseline characteristics of patients were relevant to prognosis. The study identified gene mutations in TET2 (30.9%), STAT (22.7%), RHOA (17.5%), TP53 (14.4%), DNMT3A (12.4%), with TP53 and DNMT3A mutations correlating with worse clinical outcomes. The identification of gene mutations contributed to personalizing treatment strategies and predicting patient outcomes. This study raised the preliminary hypothesis that chidamide-containing front-line therapy might be promising for PTCL patients, which warranted further investigation.