With a rise in tissue expander-based breast reconstructions (TEBRs) using acellular dermal matrix (ADM), we have seen an increase in ADM-specific complications. In this study, we aimed to evaluate clinically significant seroma (CSS) formation-defined by the need for a drainage procedure-to determine if there was a difference in incidence between product types: AlloDerm (AL), DermaMatrix (DM), and FlexHD (FHD). This was a retrospective review of consecutive patients who underwent TEBR at a single institution. The total number of reconstructed breasts was separated into the following 4 groups according to the product type: AL, DM, FHD, or no ADM. We identified the total number of CSSs and compared these data between product types. A logistic regression was performed in an attempt to identify independent risk factors associated with seroma formation. In total, we identified 284 consecutive TEBRs. Overall, there were 17 (7.7%) seromas in 220 breast reconstructions in which ADM was used. When comparing the number of CSS between groups-AL (n = 2, 4.0%), DM (n = 6, 5.4%), FHD (n = 9, 14.75%), and no ADM (n = 1, 1.5%)-we found a significant difference in seroma incidence between product types (P = 0.016). Multivariate analysis identified a strong trend toward FHD as an independent predictor of seroma formation (P = 0.061). Our review suggests that there is strong trend in CSS formation with the use of FHD as compared to other product types and reconstructions in which no ADM was used.