Extracellular nucleotides are stress-responsive ligands that mediate a variety of cellular processes via purinoceptors. We hypothesized that mechanical ventilation (MV) would alter the extracellular adenyl-nucleotide profile and purinoceptor expression in lung and extrapulmonary tissues. Twenty-eight rats were randomized to: (i) unventilated control animals; (ii) tidal volume (VT; 6 ml/kg); (iii) VT (6 ml/kg) and positive end-expiratory pressure (PEEP; 5 cm H₂0); (iv) VT (12 ml/kg); or (v) VT (12 ml/kg) and PEEP (5 cm H₂0). Bronchoalveolar lavage (BAL) was analyzed for adenyl-nucleotides. Pulmonary, hepatic, and renal tissues were assessed for P₂Y₄, P₂Y₆, P₂X₇, A₃, and A_2b receptor expression by real-time reverse transcriptase–polymerase chain reaction and Fas/Fas ligand mRNA was quantified in the lung. MV produced volume-dependent changes in BAL nucleotides; AMP and adenosine increased, whereas ATP and ADP proportions decreased. Large-volume MV increased A_2b mRNA and decreased P₂X₇ in the lung; mRNA changes in lung Fas ligand paralleled P₂X₇. PEEP normalized BAL nucleotide profiles and A_2b expression. Injurious MV reduced hepatic and renal P₂X₇ mRNA; PEEP normalized these levels in both tissues. Large-volume MV also decreased renal A_2b mRNA. MV alters the BAL adenyl-nucleotide profile and purinoceptor patterns in lung, liver, and kidney. PEEP normalizes the BAL nucleotide profile and receptor patterns in lung and extrapulmonary tissues.