Pleural infection managed with intrapleural therapy using a combination of 10 mg of tissue plasminogen activator (tPA) and 5 mg of deoxyribonuclease (DNase) has been shown in randomized and open-label studies to successfully treat >90% of patients without resorting to surgery. Potential bleeding risks, although low, and costs associated with tPA remain important concerns. No phase I studies exist for intrapleural tPA therapy and the lowest effective dose has not been established. In patients with high bleeding risks, lower doses may present a safer alternative. We report a case of a complex parapneumonic effusion in a patient with coagulopathy that was successfully treated with a very low dose tPA (1 mg) and DNase (5 mg) regime.