Subcutaneous recombinant interferon-beta1a (IFN-1a SC) is indicated for treatment of relapsing multiple sclerosis (RMS); however, it is associated with development of flu-like syndrome (FLS) in 75% of patients. No recommendations are available on whether evening or morning administration could induce better or worse FLS.Primary objective was to investigate whether morning administration of IFN-1a 44g (Rebif) would affect the severity of FLS versus evening administration, in patients with RMS. Secondary objectives were to investigate whether timing of administration could lead to a better quality of life.Multicenter, open-label, 12-week, randomized, controlled, parallel-group, phase 4 study.Of 217 patients screened at 29 Italian sites, 200 were included in the study. Among these, 104 patients were randomized to IFN-1a SC administration in the morning and 96 in the evening. Morning administration resulted in higher FLS scores, as measured by the Multiple Sclerosis Treatment Concern Questionnaire, at week 4 (p=0.0083) and week8 (p=0.0079); however, the difference was no longer significant at the end of 12weeks.IFN-1a evening injections in the first 8weeks of treatment led to an improvement in FLS; when continuing therapy, time of administration could be decided according to patient's lifestyle and preference.