Health-related quality of life (HRQOL) is an important marker for health-related impacts on individuals with chronic diseases. This HRQOL study compares multiple sclerosis (MS) patients to a socio-demographically-matched healthy control group. HRQOL was assessed by means of a modular instrument (DEFU/DEFIS), which allows comparisons between diseased and healthy individuals. Main goal of the study was to obtain pertinent data to build a more reliable theoretical framework concerning HRQOL in MS. Another aim was to test the hypothesis of the so-called happiness paradox, according to which disabled individuals could maintain reasonable levels of HRQOL. Results show that MS individuals present lower levels of HRQOL in comparison to healthy controls, arguing against the happiness paradox hypothesis. Preservation of HRQOL levels against certain levels of disability may be restricted to a group of patients.