Patients with multiple sclerosis (MS) report a number of adverse events related to immunomodulator injections, including local injection-site reactions (LISRs). Reactions characterized by pain, swelling, redness, or inflammation have been experienced by patients who self-inject glatiramer acetate, interferon beta-1b, or interferon beta-1a. Although these reactions rarely are serious, they can foster negative attitudes about self-injection and undermine a patient's commitment to treatment, especially in the early stages of therapy. This randomized crossover study of 50 patients who had initiated or restarted glatiramer acetate therapy within the 3 months before the study examined whether applying a warm compress to the injection site before self-injection would lower the incidence of LISRs compared with the patients' usual methods of injection preparation. Fewer LISRs were reported both 2 minutes and 5 minutes postinjection when warm compresses were used compared with the usual injection-site preparation (p < .001). Patients also were less bothered by LISRs when using warm compresses, as shown by mean scores on the Bothersome Scale (p = .02). Because warm compresses are easy to apply and appear to be at least modestly effective, they should be considered when recommending alternatives for patients who experience LISRs associated with glatiramer acetate. Warm compresses may be of particular benefit for those who have recently begun therapy with glatiramer acetate to help improve the likelihood of adherence to long-term treatment.