Background: Anterolateral thigh (ALT) microvascular free tissue transfer is an integral part of head and neck reconstructive surgery, but it can be complicated by postoperative donor site fluid collections. Objective: To measure the rate of hematoma and seroma formation in the ALT donor site in those treated with microporous polysaccharide hemosphere (MPH) and those without. Methods: This was a retrospective cohort study examining patients undergoing ALT free tissue transfer for head and neck reconstruction at a single academic center between 2014 and 2017. Primary outcomes were interventional hematomas and seromas and drain duration. Results: In total, 118 patients underwent ALT free flap reconstruction for head and neck defects. Of these, 57 patients received MPH at the donor site and 61 did not. Eleven patients had a clinically significant seroma in the non-MPH group compared with three in the MPH group (p = 0.045). Drain duration for the MPH group compared with that for the non-MPH group was 6.9 versus 8.2 days (p = 0.020), and drains were removed when output was <60 mL over 24 h. Conclusion: This study supports the use of MPH in ALT free flap donor sites for reduction of clinically significant postoperative seromas. Further investigation with larger prospective randomized clinical trials is warranted.