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Early military investigations of blister treatment using tissue adhesives have shown promise, finding that these agents provide pain relief, prevent infection, and allow continuation of recruit training. A trial was conducted to compare a 2-octylcyanoacrylate treatment with military standard therapy. Patients were recruited during foot evaluation at the end of a 10-km military road march. Seventy-five patients were screened, and 51 were enrolled. Twenty-six patients received 2-octylcyanoacrylate and 25 received standard treatment. A total of 80 blisters were treated (40 in each group). The mean (SD) blister size in the 2-octylcyanoacrylate group was 12.7 (6.2) mm and in the standard group was 12.0 (5.7) mm. There were no statistically significant differences in any of the baseline variables. Baseline and repeated-measures visual analog scale scores demonstrated no statistically significant differences in initial or repeat pain scores. Both groups showed a similar change across time, with a nonsignificant trend toward improvement in the standard therapy group at 10 min (28.5 versus 24.9) and in the 2-octylcyanoacrylate group at 3 days (42.9 versus 50.1). Mean Likert scores were similar, indicating no difference in patient satisfaction. Time to resumption of normal activity was similar, with one patient in each group unable to return to activity at the time of follow-up. There was a trend toward an increased proportion of patients in the 2-octylcyanoacrylate group who were able to return to normal activity within 48 hours, but this did not reach statistical significance. 2-Octylcyanoacrylate was associated with a greater degree of procedural discomfort. No infected blisters were noted in either group. (J Am Podiatr Med Assoc 96(3): 232–237, 2006)