Background: Circulating tumor cells (CTCs) are an independent prognostic factor in metastatic breast cancer (MBC). The prognostic value of CTCs and the optimal cutoff for patients (pts) with inflammatory breast cancer (IBC), one of the most aggressive types of BC, has not been fully established. Recent evidence showed the complementary prognostic value of tumor-derived extracellular vesicles (tdEVs) to CTCs in MBC. The significance of tdEVs in IBC is unexplored. This study aimed to assess the prognostic value of CTCs and tdEVs in metastatic IBC. Methods: This study retrospectively analyzed 308 pts with MBC enrolled at Northwestern University (Chicago, IL) before starting a new line of therapy between 2016 and 2021 (NU16B06 trial). Blood samples were processed for CTCs using the CellSearch system. We applied the open source ACCEPT software to archived CellSearch images to enumerate CTCs and tdEVs. TdEVs cutoff levels were <20 (low), 20-79 (intermediate), and ≥80 (high), as previously reported. The association of CTCs and tdEVs with overall survival (OS) was tested in the overall population (OvP) and IBC pts. Results: Of the 308 pts, 69 were diagnosed with IBC. 51% of pts received first-line therapy. CTCs enumerated by ACCEPT were strongly correlated with manual count (r=0.86) and hence used for this analysis. Median CTC count was 1 [interquartile range (IQR) 0-7] in IBC pts and 3 (IQR 0-14) in non-IBC (p=0.11). A significantly lower median tdEVs count was observed in IBC (7; IQR 3-45) than in non-IBC (22; IQR 4-137) pts (p=0.03). In IBC, higher CTC and tdEV counts were seen in the triple negative subtype (p=0.03) and non-visceral involvement (p=0.02), respectively. In the OvP median OS (mOS) was worse among pts with ≥5 CTCs (HR 2.6; p=0.001) and with elevated tdEVs (HR 3.3; p<0.001). Only tdEVs were independently associated with poorer OS in multivariable analysis. In pts with <5 CTCs there was a stepwise decrement in OS with increased tdEVs count (p=0.3); in pts with ≥5 CTCs, elevated tdEVs levels were associated with significantly worse OS (p=0.03). IBC pts with ≥5 CTCs had shorter mOS (8 vs 47 months; HR 3.6; p<0.001); this association was weaker using ≥1 as CTC cutoff (HR 2.4; p=0.01). OS was adversely associated with increasing tdEVs levels (33 vs 23 vs 7 months for low, intermediate, and high subgroups, respectively; HR 3.7; p=0.001). Furthermore, elevated tdEVs were associated with shorter mOS in pts with ≥1 (p=0.055) and ≥5 CTCs (p=0.6). Among pts with <5 CTCs no significant difference emerged among tdEVs subgroups (p=0.6). Conclusions: This study confirmed the strong prognostic significance of CTCs and tdEVs in MBC, including IBC. Pts with IBC had fewer CTCs and tdEVs compared to non-IBC, probably due to the predominant lymphatic spread of IBC. tdEVs offer the possibility to better define prognosis of IBC pts. Further studies are needed to evaluate their complementarity to CTCs.