Patients with multiple sclerosis often use injectable medication such as glatiramer acetate or interferons to treat their disease. Subcutaneous injections may be associated with local injection site reactions (LISRs), which can include itching, pain, swelling, or redness. Although not serious, these side effects are bothersome and can have a negative impact on adherence to the therapeutic regimen, particularly in early phases of treatment. This randomized parallel group study of 83 patients with multiple sclerosis who had recently begun glatiramer acetate therapy investigated whether administration of an oral antihistamine (cetirizine hydrochloride; Zyrtec, 10 mg) prior to each daily subcutaneous injection of glatiramer acetate would lower the incidence of LISRs compared with an oral placebo. Data for the outcome measures were derived from patient diaries and from the clinic during the baseline and the treatment periods. The primary outcome measure comparing the number of LISRs at 5 minutes after injection over 2 weeks was slightly but not significantly lower in patients who received cetirizine compared with patients who received placebo. Within-group comparisons showed that there was a significant reduction in mean LISR score from the 2-week baseline period to the 2-week cetirizine treatment period (0, 2, and 5 minutes after treatment). Both groups showed decreases in the average bothersome ratings from the baseline to treatment periods. Use of cetirizine did not affect the type of LISRs that was reported at any time point. There were no safety concerns with the concurrent administration of cetirizine with glatiramer acetate. Because there were no statistically significant differences on the primary end point between patient groups taking cetirizine and those taking placebo prior to glatiramer acetate injections, cetirizine use as a strategy to reduce LISRs in patients on glatiramer acetate therapy cannot be recommended at this time.