To analyse the expression and clinical role of the phosphatase PTPN1 (PTP1B) in serous effusions. PTPN1 mRNA expression by quantitative RT-PCR was analysed in 83 high-grade serous carcinoma (HGSC) and 15 malignant mesothelioma (MM) effusions. PTP1B and phospho-PTP1B (pPTP1B) protein expression by immunohistochemistry was analysed in 62 HGSC and 44 MM effusions. PTPN1 mRNA (P=.048), PTP1B protein (P=.047) and pPTP1B protein (P<.001) were overexpressed in HGSC compared to MM effusions. PTPN1 mRNA was additionally overexpressed in post-chemotherapy HGSC effusions compared to chemo-naïve effusions (P=.005). However, pPTP1B protein expression was higher in effusions from patients with FIGO stage III compared to stage IV (P=.006), and higher expressions of both PTPN1 mRNA (P=.041) and PTP1B protein (P=.035) in HGSC effusions were associated with better (complete) chemotherapy response at diagnosis. PTPN1 RNA and protein expression was unrelated to survival in HGSC, whereas a trend for shorter overall survival (P=.06) was found for MM patients whose tumours expressed pPTP1B protein. PTPN1 is overexpressed in HGSC compared to MM effusions, and may be a marker of better chemotherapy response in the former. Whether PTPN1 activation is informative of adverse outcome in MM merits further investigation.