Objective Talc slurry pleurodesis (TSP) can lead to permanent small loculations. Intrapleural tissue plasminogen activator (tPA) breaks down loculations, and therefore may improve results but may also inhibit pleurodesis. tPA was given with and after talc slurry to promote more uniform talc distribution and eliminate loculations. Methods Charts were reviewed for patients treated with TSP with or without tPA. Chest x-rays after TSP were compared to chest x-rays before and graded as "worse", "same", or "better". Incidence of need for repeat TSP was recorded. Results There were 52 patients, eight with bilateral effusions, for a study cohort of 60 effusions. One-third of the effusions were malignant. No patients experienced significant bleeding. Results were better than baseline for 14 (26%) patients given tPA, but not for patients that never received tPA. The addition of tPA 4-6 mg with talc slurry resulted in no patients requiring repeat TSP. When tPA was given after talc slurry, a delay of three days was associated with the lowest incidence of repeat TSP (3/14, 21%). Conclusions There were no significant complications from tPA use to supplement TSP, and tPA may improve results without interfering with pleurodesis. A prospective trial is warranted.