Background: Several interferon beta (IFNβ) formulations are approved for first-line use as disease-modifying therapies to treat patients with multiple sclerosis (MS). Systemic post-injection reactions, often termed flu-like symptoms (FLS), occur in approximately half of all patients treated with IFNβs and can affect adherence to therapy. These symptoms, which include pyrexia, chills, malaise, myalgia, and headaches, usually resolve within 24 hours or persist intermittently following each injection. Because FLS, which usually occur early in the treatment course and diminish over time, are a primary cause of nonadherence to IFNβ therapy, it is important to employ strategies that can attenuate these side effects. Methods: To identify interventions effective in limiting FLS, a panel of United States–based nurses with expertise in MS patient care was convened and a literature review completed. Results: Panel consensus was reached on specific interventions that can attenuate FLS. These prevention and mitigation strategies include dose titration, analgesia, and optimal injection timing, as well as other techniques that panel members have found useful in their clinical practice experience. Conclusions: These measures, in addition to effective patient education, will help to reduce the incidence of FLS secondary to IFNβ therapy, improve patient medication adherence, and positively affect long-term clinical outcomes.