Peripheral T-cell lymphoma (PTCL) is characterized by an aggressive clinical behavior. Chidamide has been approved for the treatment of relapsed/refractory (R/R) PTCL in China. We compared the efficacy of chidamide-contained regimens with chemotherapy (ChT) in R/R PTCL. Based on the second-line treatments, patients were divided into three groups, including ChT, ChT combined with chidamide (chidamide + ChT) and chidamide combined with or without other targeted agents (targeted therapy) group. Chidamide + ChT group had a better progression-free survival (PFS) compared with targeted therapy group (p = 0.013), and showed a trend towards superior PFS compared with ChT group (p = 0.079). Among patients with high second-line International Prognostic Index (IPI) (3-5), chidamide+ChT group had a longer PFS than ChT group(p = 0.018), and PFS in targeted therapy group was not inferior to that in chidamide+ChT group (p = 0.200). Among patients younger than 60 years, chidamide+ChT group demonstrated a PFS benefit over targeted therapy group (p = 0.010). Among CD30-negative patients, PFS was superior in the chidamide+ChT group compared with ChT group (p < 0.001). Conversely, results observed above were absent in patients with low second-line IPI or patients older than 60 years or CD30-positive patients. Overall, the combination of chidamide and ChT may be an effective treatment strategy for R/R PTCL.