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Pirarubicin is an analog of doxorubicin. Few studies have compared the long-term outcomes of patients receiving pirarubicin-based THP-COP and doxorubicin-based CHOP in the treatment of non-Hodgkin's lymphoma (NHL). We retrospectively compared the efficacy and safety of these two regimens in 459 previously untreated aggressive NHL patients admitted to Sun Yat-Sen University Cancer Center from 1987 to 2003. For initial treatment, 205 patients received the THP-COP regimen, and 254 patients received the CHOP regimen. The patients' characteristics were well balanced. The groups did not differ in the complete remission rate (THP-COP, 57.1% vs. CHOP, 57.0%; P = 0.998) or response rate (THP-COP, 82.9% vs. CHOP, 81.5%; P = 0.691). At a median follow-up of 95.7 months, the 8-year survival rates were also similar (overall survival: THP-COP, 55.8% vs. CHOP, 56.7%; progression-free survival: THP-COP, 47.3% vs. CHOP, 43.5%; lymphoma-specific survival: THP-COP, 51.2% vs. CHOP, 48.5%). The THP-COP group had fewer cases of alopecia (P < 0.001) and gastrointestinal toxicities (P = 0.015). A tendency toward decreased arrhythmia (P = 0.075), especially in elderly patients (P = 0.030), was found. In combination chemotherapy for aggressive NHL, pirarubicin has comparable efficacy to doxorubicin and has a lower incidence of alopecia, gastrointestinal toxicities, and arrhythmia. Further studies are warranted to confirm these results.