We report two trials describing whether talc pleurodesis with a mean particle size of less than 15 microm ("mixed" talc) produces more lung and systemic inflammation than tetracycline or "graded" talc (most particles < 10 microm were removed). First, 20 patients with malignant effusions received tetracycline or mixed talc. Changes in lung and systemic inflammation from lung clearance scans, oxygen saturations, and C-reactive protein from baseline to 48 hours after pleurodesis were recorded. Lung inflammation (change in isotope clearance, talc -9.26, SD 14.3 vs. tetracycline 4.10, SD 13.8 minutes; difference = -13.4; 95% confidence interval [CI], -26.6 to -0.2; p = 0.05) and systemic inflammation (change in C-reactive protein, talc 198 SD 79.2 vs. tetracycline 74 SD 79.4 microg/L; difference = 124; 95% CI, 50 to 199; p = 0.004) were greater after talc. Second, 48 patients received mixed or graded talc, and gas exchange was assessed from changes in the alveolar-arterial oxygen gradient. Mixed talc worsened gas exchange (oxygen gradient change, mixed 2.17 SD 1.74 kPa, 16.3 13.1 mm Hg vs. graded 0.72 SD 2.46 kPa 5.4 18.5 mm Hg, difference = 1.45; 95% CI, 0.2 to 2.7; p = 0.03) and induced more systemic inflammation than graded talc. We conclude that the routine use of graded talc for pleurodesis would reduce the morbidity of this procedure.