The effects of doxycycline hyclate (DOXY) pleurodesis were compared with those of tetracycline hydrochloride (TCN) in 25 healthy New Zealand White rabbits. One group of rabbits received TCN (pH 2.0) in the left pleural space at a concentration of 35 mg/kg in 3.0 ml of saline solution. Four other groups of rabbits received DOXY in two concentrations (35 mg/kg or 10 mg/kg) and at two pHs (an acid of 2.0 and a NaOH neutralized pH of 7.6). No attempt was made to drain the pleural space after pleurodesis. At autopsy 2 weeks later, bloody fluid filled the pleural cavity and extensive intrapleural adhesions compressed the underlying lung. Microscopically, fibrin and collagen were diffusely deposited in the pleural connective tissue and in the intrapleural adhesions. The visceral pleural thickness increased from its normal value of 0.01 mm to values of 0.5 to 0.9 mm in the TCN and DOXY groups. Fibroblasts were the predominant inflammatory cell in the pleural connective tissue with few neutrophils or lymphocytes. No significant differences of histologic characteristics were observed between the TCN and DOXY groups. Alterations in pH or concentration in the DOXY groups produced similar changes in the gross and microscopic appearance of the pleural space. We conclude that DOXY is as effective as TCN in producing chemical pleurodesis. Doxycycline concentrations of 10 mg/kg were sufficient to substantially sclerose the pleural space in these healthy rabbits. Doxycycline pleurodesis was effective at neutral pH suggesting a mechanism of action independent of acid injury to the mesothelium.