INTRODUCTION: Reduced quality of life (QoL) is an early feature of multiple sclerosis (MS). The effect of progression independent of relapse activity (PIRA) on QoL is poorly investigated. OBJECTIVE: To assess the impact of PIRA on QoL using patient-reported outcome measures (PROMs). METHODS: In a prospective observational study, 125 newly diagnosed persons with relapsing-remitting MS (PwRRMS) were assessed over 5 years with: EuroQoL-5-Dimension-3-level (EQ-5D-3L), EQ-visual-analogous-scale (EQ-VAS) and 29-item-MS-Impact-Scale (MSIS-29). PwRRMS were dichotomized: PIRA (worsening of expanded disability status scale (EDSS), timed-25-foot-walk or 9-hole-peg-test, independent of relapses) versus non-PIRA. PwRRMS were compared at baseline, year 5 (y5) and delta values (baseline scores subtracted from y5 scores) and annually using linear-mixed-effects-models. RESULTS: At y5, 19.2% had PIRA. PIRA versus non-PIRA PwRRMS were older ( CONCLUSION: Deteriorating QoL in the early course of relapsing-remitting multiple sclerosis (RRMS) is strongly associated with PIRA. Our results suggest that QoL PROMs should be monitored and recognized as an important aspect of progression.