Purpose: To assess the impact of cryotherapy or topical minocycline on patients' perceptions of recovery from pain after third molar surgery in an exploratory comparative-effectiveness study. Patients and Methods: Subjects aged at least 14 years who were having all 4 third molars removed were enrolled in 3 separate institutional review boardapproved studies. Study groups included subjects treated with a passively applied cold wrap for 24 hours postoperatively, subjects treated with topical minocycline during surgery, and subjects enrolled in a nonconcurrent comparison group who had received neither topical minocycline nor directed cryotherapy. Third molar surgery was performed in all cases by trained surgeons using the same protocol. An exact Kruskal-Wallis test was used to compare the distributions of the worst and average pain scores and a Fisher exact test to compare verbal responses from Gracely pain scales among the 3 groups for postsurgical days (PSDs) 1 to 3. Results: This study comprised 51 cryotherapy subjects (2005-2009), 63 minocycline subjects (2003-2004), and 92 comparison-group subjects (2002-2006) who were treated at academic centers and in community practices across the United States (N = 206). Demographic descriptors were similar among all groups. For PSDs 1 through 3 (unadjusted), the highest scores for worst pain (6-7 [out of 7] on Likert-type scale) were reported less frequently in each of the study groups than in subjects in the comparison group, although the numbers of subjects reporting the highest scores were few. The distribution of pain outcomes was significantly different among the 3 groups for worst pain and affective words on PSD 1 (P =.04 for both). However, the small number of subjects who reported the highest pain scores precluded adequate multivariate statistical analyses for all outcomes on PSD 1 to 3. Conclusions: Data from this exploratory study suggest that adjunctive therapy to decrease postoperative paincryotherapy or topical minocyclinemight be effective at moderating the patient's highest pain levels after third molar surgery. The topic should be studied further in a multicenter, prospective, randomized trial. © 2011 American Association of Oral and Maxillofacial Surgeons.