P latelet activation is a hallmark of severe preeclampsia, and platelet PGH synthase 1–derived (PGHS1-derived) thromboxane A₂ (TxA₂) has been implicated in its pathogenesis. However, genetic disruption of PGHS1 delays parturition. We created hypomorphic PGHS1 (PGHS1^Neo/Neo) mice, in which the substantial but tissue-dependent variability in the inhibition of PGHS1-derived eicosanoids achieved by low-dose aspirin treatment is mimicked, to assess the relative impact of this strategy on hemostatic and reproductive function. Depression of platelet TxA₂ by 98% in PGHS1^Neo/Neo mice decreased platelet aggregation and prevented thrombosis. Similarly, depression of macrophage PGE₂ by 75% was associated with selectively impaired inflammatory responses. PGF_2α at 8% WT levels was sufficient to induce coordinated temporal oxytocin receptor (OTR) expression in uterus and normal ovarian luteolysis in PGHS1^Neo/Neo mice at late gestation, while absence of PGHS1 expression in null mice delayed OTR induction and the programmed decrease of serum progesterone during parturition. Thus, extensive but tissue-dependent variability in PG suppression, as occurs with low-dose aspirin treatment, prevents thrombosis and impairs the inflammatory response but sustains parturition. PGHS1^Neo/Neo mice provide a model of low-dose aspirin therapy that elucidates how prevention or delay of preeclampsia might be achieved without compromising reproductive function.