Background: Extracellular adenosine 5'-triphosphate (ATP) is involved in the regulation of a variety of biologic processes, including neurotransmission, muscle contraction, and liver glucose metabolism, via purinergic receptors, In nonrandomized studies involving patients with different tumor types including non-small-cell lung cancer (NSCLC), ATP infusion appeared to inhibit loss of weight and deterioration of quality of life (QOL) and performance status. We conducted a randomized clinical trial to evaluate the effects of ATP in patients with advanced NSCLC (stage IIIB or IV). Methods: Fifty-eight patients were randomly assigned to receive either 10 intravenous 30-hour ATP infusions, with the infusions given at 2- to 4-week intervals, or no ATP, Outcome parameters were assessed every 4 weeks until 28 weeks. Between-group differences were tested for statistical significance by use of repeated-measures analysis, and reported P values are two-sided. Results: Twenty-eight patients were allocated to receive ATP treatment and 30 received no ATP, Mean weight changes per 4-week period were -1.0 kg (95% confidence interval [CI] = -1.5 to -0.5) in the control group and 0.2 kg (95% CI = -0.2 to +0.6) in the ATP group (P = .002). Serum albumin concentration declined by -1.2 g/L (95% CI = -2.0 to -0.4) per 4 weeks in the control group but remained stable (0.0 g/L; 95% CI = -0.3 to +0.3) in the ATP group (P = .006). Elbow flexor muscle strength declined by -5.5% (95% CI = -9.6% to -1.4%) per 4 weeks in the control group but remained stable (0.0%; 95% CI = -1.4% to +1.4%) in the ATP group (P = .01). A similar pattern was observed far knee extensor muscles (P = .02). The effects of ATP on body weight, muscle strength, and albumin concentration were especially marked in cachectic patients (P = .0002, P = .0001, and P = .0001, respectively, for ATP versus no ATP). QOL score changes per 4-week period in the ATP group showed overall less deterioration than in the control group-physical scores (-0.2% versus -2.4%; P = .0002); functional scores (+0.4% versus -5.5%; P = .02); psychologic scores (-0.7% versus -2.4%; P = .11); overall QOL score (+0.1% versus -3.5%; P = .0001). Conclusions: This randomized trial demonstrates that ATP has beneficial effects on weight, muscle strength, and QOL in patients with advanced NSCLC.