(R)-CHOP-14 has substantially improved outcome in DLBCL, but may have increased morbidity and reduced quality of life (QoL). Our aim was to evaluate QoL during (R)-CHOP-14-based chemotherapy. Twenty-six patients participated (small single-center study). EORTC QLQ-C30 was completed pre-treatment, mid-treatment, 14 days post-treatment, and 3 months post-treatment. Scores were compared to a reference population, and analyzed separately. Pre-treatment, global health status (p = 0.004), physical functioning (p = 0.036), role functioning (p = 0.017), and emotional functioning (p = 0.040) were reduced, and fatigue (p = 0.009) and appetite loss (p = 0.007) increased compared to the reference population. During treatment, physical functioning and role functioning decreased significantly, whereas emotional functioning, fatigue, and diarrhea increased. Three months post-treatment, scores were generally equivalent to those of the reference population, and lower for nausea/vomiting (p < 0.001) and constipation (p < 0.001). Disease-related symptoms were frequent in high-risk DLBCL. Treatment-related symptoms were normalized 3 months post-treatment. In conclusion, QoL is only temporarily affected during (R)-CHOP-14-based chemotherapy, and the treatment regimen is therefore feasible.