Delivery of drugs by airway can minimize systemic toxicity and maximize local drug concentrations. Most cancers metastasize to the lungs. Our purpose was to determine platinum concentrations in the lung after targeted delivery of cisplatin (CDDP) with an intracorporeal nebulizing catheter (INC), and to determine the safety of escalating doses of inhaled CDDP. In anesthetized and mechanically ventilated healthy dogs, the INC (AeroProbe) was introduced via flexible bronchoscope into the right caudal lung lobe (RCLL) and CDDP (10 mg/m2) administered. Tissue and serum platinum concentrations were compared to those after an equivalent intravenous dose of CDDP (n = 3 dogs/group). In three additional dogs, pharmacokinetics were performed after inhaled and intravenous CDDP. Increasing dosages of inhaled CDDP (10, 15, 20, and 30 mg/m2) were then administered every 2 weeks. Dogs were sacrificed for postmortem examination at week 10. One additional dog was treated with a single dose of 30 mg/m2 and sacrificed 2 weeks later. Immediately following a single inhaled dose, mean CDDP levels were 44 times greater in the RCLL than in most other tissues and 15.6 times lower in the serum compared to intravenous dosing. Pharmacokinetic comparison showed that the AUC0-24h was similar (p = 0.72), but maximum serum concentration was fivefold lower after inhalation than intravenous delivery (p = 0.02). Escalating doses of inhaled CDDP (cumulative 75 mg/m2) produced no significant clinical or hematological effects, but there was radiographic and histologic evidence of severe pneumonitis with mild to moderate fibrosis confined to the RCLL. Radiographic and histologic changes were similar in the single, high-dose dog. Targeted inhaled CDDP achieved high concentrations in the treated lobe, with lower peak serum levels than after intravenous administration. Escalating doses of inhaled CDDP produced focal pneumonitis and fibrosis in the treated lung lobe with minimal clinical and hematologic effects. Targeted inhaled chemotherapy could be a promising method of treatment for primary and secondary lung tumors.