OBJECTIVES:  The survival benefits of nal-IRI+5-fluorouracil/leucovorin vs 5-fluorouracil/leucovorin in mPC patients who progressed after prior gemcitabine-based therapy were demonstrated in a phase 3 study (NAPOLI-1); preplanned analyses of QoL demonstrated no differences between treatment groups. While chemotherapy causes toxicities that impair HR-QoL, its clinical benefits may improve HR-QoL. We conducted a post hoc analysis of NAPOLI-1 EORTC-QLQ-C30 questionnaire measures to compare overall HR-QoL change. METHODS:  A principal component (PC) analysis was performed on the EORTC-QLQ-C30 scales week-6 changes. PC scores were compared between groups, and correlations between EORTC-QLQ-C30 scale increments examined. RESULTS:  Of 266 randomized patients, 122 had baseline and week-6 EORTC-QLQ-C30 scale measures and were included in the analysis. EORTC-QLQ-C30 increments in pain (–8.0 vs +9.0; P=0.0060), insomnia (–10.3 vs +9.5; P=0.0023), role functioning (–0.3 vs –11.7; P=0.0346), and Global Health Status/Quality of Life (GHS/QL; +0.6 vs –8.2; P=0.0318) favored patients receiving nal-IRI+5-fluorouracil/leucovorin vs 5-fluorouracil/leucovorin alone. No differences favored patients receiving 5-fluorouracil/leucovorin (P-values ≥0.1039), although diarrhea scores were numerically lower (+15.4 vs +6.7). GHS/QL increments were not correlated with diarrhea (P=0.8487), nausea/vomiting (P=0.3787), constipation (P=0.3255), or dyspnea (P=0.3253); pain (P<0.0001), fatigue (P<0.0001), insomnia (P<0.0002), and appetite loss (P<0.0002) were. Role functioning change had the strongest positive correlation with GHS/QL increment (+0.39, P<0.0001). Multivariate comparison of the first 4 EORTC-QLQ-C30 scales changes PCs (variance explained: 59%) found treatment groups to be different (P=0.0051). With positive weights on functioning and GHS/QL scales, and negative weights on symptoms and financial difficulties scales, the first PC (explained variance: 34%) reflected general HR-QoL. nal-IRI+5-fluorouracil/leucovorin patients (vs. 5-fluorouracil/leucovorin) had higher first PC score (P=0.0478). CONCLUSIONS:  Results of this post hoc analysis suggest that nal-IRI+5-fluorouracil/leucovorin improves HR-QoL vs 5-fluorouracil/leucovorin alone, and that certain chemotherapy adverse effects are not associated with HR-QoL detriments.