Alveolar fibrocytes are monocyte-derived mesenchymal cells associated with poor prognosis in patients with acute respiratory distress syndrome. Our aims were to determine the following: 1) the ability of monocytes from acute respiratory distress syndrome patients to differentiate into fibrocytes; 2) the influence of the acute respiratory distress syndrome alveolar environment on fibrocyte differentiation; and 3) mediators involved in this modulation, focusing on serum amyloid P. Design: Experimental in vitro investigation. Setting: Two ICUs of a teaching hospital. Patients: Twenty-five patients (19 mild-to-severe acute respiratory distress syndrome and six matched ventilated controls without acute respiratory distress syndrome) were enrolled. Six healthy volunteers served as non-ventilated controls. Interventions: Peripheral blood mononuclear cells were isolated from acute respiratory distress syndrome, ventilated controls, and non-ventilated controls blood and cultured in vitro. Fibrocytes were counted at basal condition and after culture with bronchoalveolar lavage fluid. Plasma and broncho-alveolar lavage fluid serum amyloid P contents were determined by western blot and enzyme-linked immunosorbent assay. Serum amyloid P was located in normal and acute respiratory distress syndrome lung by immunohistochemistry. Measurements and Main Results: Acute respiratory distress syndrome peripheral blood mononuclear cells had a threefold increased ability to differentiate into fibrocytes compared to ventilated controls or non-ventilated controls. Acute respiratory distress syndrome broncho-alveolar lavage fluid inhibited by 71% (55-94) fibrocyte differentiation compared to saline control. Ventilated controls' broncho-alveolar lavage fluid was a less potent inhibitor (51% [23-66%] of inhibition), whereas non-ventilated controls' broncho-alveolar lavage fluid had no effect on fibrocyte differentiation. Serum amyloid P concentration was decreased in plasma and dramatically increased in broncho-alveolar lavage fluid during acute respiratory distress syndrome. Alveolar serum amyloid P originated, in part, from the release of serum amyloid P associated with lung connective tissue during acute respiratory distress syndrome. Serum amyloid P depletion decreased the inhibitory effect of acute respiratory distress syndrome bronchoalveolar lavage fluid by 60%, whereas serum amyloid P replenishment of serum amyloid P-depleted acute respiratory distress syndrome broncho-alveolar lavage fluid restored their full inhibitory effect. Conclusions: The presence of fibrocytes in the lung during acute respiratory distress syndrome could result in a balance between