We previously reported the therapeutic efficacy of 13-cis retinoic acid (13-cRA) in some subtypes of peripheral T-cell lymphoma (PTCL). This study sought to clarify if the addition of interferon-alpha2a (IFN-alpha2a), an agent with synergistic cytotoxicity with 13-cRA in many types of malignant cells, may be more effective in the treatment of PTCL. Eligible patients has histologically proven PTCL, which was recurrent after or refractory to anthracycline-containing systemic chemotherapy. The treatment included oral administration of 13-cRA 1 mg/kg/day, divided into three doses, and intramuscular injection of IFN-alpha2a 4.5 MU/M2, three times per week. From March 1995 to July 2000, a total of 17 patients, 10 men and 7 women, with a median age of 47 years (range, 18-77 years), were recruited. The histologic diagnosis included 7 cases of unspecified PTCL, 6 cases of Ki-1 anaplastic large cell lymphoma (ALCL), 1 case of angioimmunoblastic T-cell lymphoma, and 3 cases of angiocentric nasal NK/T cell lymphoma. They received a median of 1.7 months of treatment (range, 0.4-13.3 months). One patient refused further treatment due to toxicity. The doses of 13-cRA and IFN-alpha2a had to be decreased in 7 and 7 patients, respectively. Grade III/IV hematologic and non-hematologic toxicity developed in 2 and 5 patients, respectively. There were 5 partial responses (Ki-1, 4; unspecified PTCL, 1), with a total response rate of 31.3% (95% CI, 5.7-56.8%). The median duration of response for the responders was 2.5 months (range, 0.8-7.2 months). The median overall survival for the entire group of patients was 3.6 months. In conclusion, a combination of 13-cRA and IFN-alpha2a is a useful salvage treatment for selected patients with recurrent or refractory PTCL, particularly those with the Ki-1 subtype. However, the data does not support that addition of IFN-alpha2a is superior to 13-cRA alone.