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• Predictors of six-month change in physical and mental HRQoL were investigated. • Predictors were assessed at clinic entry for a three-week rehabilitation stay. • Physical HRQoL and depressive mood predicted six-month change in physical HRQoL. • Mental HRQoL and time since diagnosis predicted six-month change in mental HRQoL. • The regression models explained 18.6 % (physical) and 26.8 % (mental) of the variance. Symptomatic treatment in people with multiple sclerosis (pwMS) requires multidisciplinary rehabilitation to alleviate disease progression and increasing health-related quality of life (HRQoL). However, the participant- and disease-specific factors that predict sustained improvement in HRQoL in pwMS undergoing inpatient rehabilitation remain unclear. Identifying these factors can help individually tailor inpatient rehabilitation programmes. Therefore, the aim of this study was to identify factors of pwMS at clinic entry for a three-week multidisciplinary inpatient rehabilitation that predict the change in physical and mental HRQoL over six months. This is a secondary data analysis of a randomized controlled trial (NCT04356248) conducted at the Valens Rehabilitation Centre, Switzerland. HRQoL was assessed with the Medical Outcome Study 36-item Short Form Health Survey (SF-36) at clinic entry (T 0 ; baseline) and six months after (T 3 ; six-month follow-up). Data for 99 pwMS (mean age in years: 49.60 ± 10.17 SD, mean Expanded Disability Status Scale (EDSS) score: 4.62 ± 1.33 SD, 68.7 % female) were analysed using multiple linear regression. Outcome variables were six-month change in SF-36 Physical (ΔPCS) and Mental Component Scale (ΔMCS) scores. Predictor variables included baseline scores of PCS or MCS, fatigue, anxiety, depressive mood, cardiorespiratory fitness (V̇O 2peak/kg), self-efficacy, smoking status, education level, age, EDSS, sex, time since diagnosis and MS phenotype. The regression model with ΔPCS as outcome variable explained 18.6 % of the variance of the ΔPCS score (p =.003). Lower PCS score (p <.001) and lower depressive mood (p =.032) at baseline predicted higher ΔPCS score. The regression model with ΔMCS as outcome variable explained 26.8 % of the variance of the ΔMCS score (p <.001). Lower MCS score (p <.001) and longer time since diagnosis (p =.048) at baseline predicted higher ΔMCS score. PwMS with lower physical HRQoL and better mood at clinic entry improved most in physical HRQoL over six months. PwMS with lower mental HRQoL and longer time since diagnosis at clinic entry improved most in mental HRQoL over six months. The results of this study contribute to the development of individualized rehabilitation programmes with the aim of maintaining and/or improving HRQoL of pwMS beyond the inpatient rehabilitation stay. [ABSTRACT FROM AUTHOR]