The objective of this study was to analyze the expression and clinical role of Wnt pathway molecules in metastatic high-grade serous carcinoma (HGSC). mRNA expression by qPCR of 20 molecules related to Wnt signaling (WNT1, WNT2, WNT3, WNT4, WNT5A, WNT6, WNT7, WNT11, FZD1, FZD4, FZD5, FZD6, FZD7, FZD8, FZD10, LRP5, LRP6, DKK, CCND, RUNX2) was analyzed in 87 HGSC effusions. Thirty-nine surgical specimens (19 ovarian, 20 from other intra-abdominal sites) were analyzed for comparative purposes. Protein expression of YAP and LRP and their phosphorylated forms by western blotting were analyzed in 52 tumors. Significant differences in mRNA expression as a function of the anatomic site were observed for WNT3 (p = 0.005), WNT5A (p = 0.008), WNT7 (p < 0.001), FRZ5 (p = 0.04), and FRZ6 (p < 0.001). YAP and LRP and their phosphorylated forms were detected in HGSC specimens. FZD10 was overexpressed in effusions from patients who had complete response to chemotherapy compared with those with less favorable response (p = 0.037). WNT4 (p = 0.005), WNT7 (p = 0.047), RUNX2 (p = 0.038), LRP5 (p = 0.022), LRP6 (p = 0.011), FZD6 (p = 0.036), FZD7 (p = 0.004), and FZD10 (p = 0.015) levels were inversely related to primary chemoresistance. High FZD5 levels in pre-chemotherapy effusions tapped at diagnosis and high WNT2 levels in post-chemotherapy disease recurrence effusions were related to shorter overall survival (p = 0.018 and p = 0.011, respectively), whereas high RUNX2 (p = 0.031) and FZD1 (p = 0.029) in post-chemotherapy effusions were associated with longer overall survival. In multivariate analysis of post-chemotherapy cases, WNT2 (p = 0.002), RUNX2 (p = 0.017), FZD1 (p = 0.036), and FZD4 (p = 0.013) were independent prognosticators. In conclusion, expression of Wnt pathway molecules is anatomic site dependent. In HGSC effusions, it is informative of chemoresponse and survival.