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Abstract Background The current standard of care for non‐bulky diffuse large B‐cell lymphoma (DLBCL) patients with an International Prognostic Index (IPI) of 0 is four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) but whether the same efficacy can be achieved with reduced chemotherapy regimen of four cycles for non‐bulky DLBCL patients with an IPI of 1 remains unclear. This study compared four cycles versus six cycles of chemotherapy in non‐bulky low‐risk DLBCL patients with negative interim positron emission tomography with computed tomography (PET‐CT, Deauville 1‐3), irrespective of age and other IPI risk factors (IPI 0‐1). Methods This was an open‐label, randomized, phase III, non‐inferiority trial. Patients aged 14‐75 years with newly diagnosed low‐risk DLBCL, according to IPI, achieving PET‐CT confirmed complete response (CR) after four cycles of R‐CHOP were randomized (1:1) between four cycles of rituximab (4R‐CHOP+4R arm) or two cycles of R‐CHOP plus two cycles of rituximab (6R‐CHOP+2R arm). The primary endpoint was 2‐year progression‐free survival (PFS), conducted in the intention‐to‐treat population. Safety was assessed in patients with at least one cycle of assigned treatment. The non‐inferiority margin was ‐8%. Results A total of 287 patients were included in the intention‐to‐treat analysis, the median follow‐up was 47.3 months, and the 2‐year PFS rate was 95% (95% confidence interval [CI], 92% to 99%) and 94% (95% CI, 91% to 98%) for the 4R‐CHOP+4R and 6R‐CHOP+2R arm. The absolute difference in 2‐year PFS between the two arms was 1% (95% CI, ‐5% to 7%), supporting the non‐inferiority of 4R‐CHOP+4R. Grade 3‐4 neutropenia was lower in the last four cycles of rituximab alone in the 4R‐CHOP+4R arm (16.7% versus 76.9%), with decreased risk of febrile neutropenia (0.0% versus 8.4%) and infection (2.1% versus 14.0%). Conclusions For newly diagnosed low‐risk DLBCL patients, interim PET‐CT after four cycles of R‐CHOP was effective in identifying patients with Deauville 1‐3 who would have a good response and Deauville 4‐5 patients who might have high‐risk biological features or develop resistance. Reducing the standard six cycles to four cycles of chemotherapy had comparable clinical efficacy and fewer adverse events in low‐risk, non‐bulky DLBCL with interim PET‐CT confirmed CR.