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Problem: Persistent hypoxia and inflammation beyond early pregnancy are involved in a bad outcome because of defective trophoblast invasiveness. Tissue transglutaminase (TG2) coregulates several cell functions. An aberrant expression and/or transamidation activity could contribute to placental dysfunction. Method of study: The first‐trimester trophoblast cell line (Swan‐71) was used to study TG2 expression and cell functions in the absence or presence of inflammatory cytokines (TNF‐α, IL‐1β) or chemical hypoxia (CoCl2). We analyzed The concentration of cytokines in the supernatant by ELISA; Cell migration by scratch assay; NF‐κB activation by detection of nuclear p65 by immunofluorescence or flow cytometry using a Swan‐71 NF‐κB‐hrGFP reporter cell line. Tissue transglutaminase expression was analyzed by immunoblot and confocal microscopy. Expression of spliced mRNA variants of tissue transglutaminase was analyzed by RT‐PCR. Transamidation activity was assessed by flow cytometry using 5‐(biotinamido)‐pentylamine substrate. Results: Chemical hypoxia and TGase inhibition, but not inflammatory stimuli, decreased Swan‐71 migration. IL‐6 production was also decreased by chemical hypoxia, but increased by inflammation. Intracellular TGase activity was increased by all stimuli, but NF‐κB activation was observed only in the presence of proinflammatory cytokines. TG2 expression was decreased by CoCl2 and TNF‐α. Translocation of TG2 and p65 to nuclei was observed only with TNF‐α, without colocalization. Differential relative expression of spliced variants of mRNA was observed between CoCl2 and inflammatory stimuli. Conclusion: The observed decrease in total TG2 expression and relative increase in short variants under hypoxia conditions could contribute to impaired trophoblast invasion and impact on pregnancy outcome. [ABSTRACT FROM AUTHOR]