The aim of this study was to evaluate the effectiveness of topical 60% dimethyl sulphoxide (DMSO) prior to tissue expansion for breast reconstruction in reducing expander pressure and length of treatment. Forty patients undergoing immediate breast reconstruction with tissue expanders following modified radical mastectomy were consecutively divided into two groups of 20 subjects each: group A (control) and group B (experimental). Patients from group A underwent traditional tissue expansion, while, to patients of group B, before each filling session, topical 60% DMSO was applied to the skin overlying the expander by soaking-wet surgical sponges left in place for 30 min. The average inflated volume was 395 cc (range 250–580 cc) in group A, and 410 cc (range 240–620 cc) in group B; no statistically significant difference was found between these values. A statistically significant difference was found between the expansion time of group A (mean 6 sessions; range 4–10 sessions with one filling session per week) and group B (mean 4 sessions; range 2–6 sessions with one filling session per week). A statistically significant difference was also found between the average inflated volume per session of group A (90 cc; range 60–130 cc) and group B (120 cc; range 90–160 cc). According to the data obtained by tonometry, a statistically significant difference was found between the average pre-filling and post-filling pressures of group A (28.4 and 66.5 mmHg, respectively) and group B (22.1 and 64.3 mmHg, respectively). Clinical benefits of pre-filling topical applications of 60% DMSO observed in our trial were an enhancement of the total volume inflatable per session and a significant shortening of the total expansion period.