Grape seed procyanidin extract (GSE) had been reported to exert antineoplastic properties in preclinical studies. A modified phase I, open-label, dose-escalation clinical study was conducted to evaluate the safety, tolerability, maximum tolerated dose (MTD), and potential chemopreventive effects of leucoselect phytosome (LP), a standardized GSE complexed with soy phospholipids to enhance bio-availability, in heavy active and former smokers. Eight subjects age 46 - 68 were enrolled into the study and treated with escalating oral doses of LP for 3 months. Bronchoscopies with bronchoalveolar lavage (BAL) and bronchial biopsies were performed before and after 3 months of LP treatment. H&E stain for histopathology grading and immunohistochemical examination for Ki-67 proliferative labeling index (KI-67 LI) were carried out on serially matched bronchial biopsy samples from each subject to determine responses to treatment. Two subjects were withdrawn due to issues unrelated to the study medication, and a total of 6 subjects completed the full study course. In general, three months of LP, reaching the highest dose per study protocol was well tolerated and no dosing adjustment was necessary. Such a treatment regimen significantly decreased bronchial Ki-67 LI by an average of 55% (p = 0.041), with concomitant decreases in serum microRNA (miR)-19a, -19b and -106b, which were oncomirs previously reported to be downregulated by GSE, including LP, in pre-clinical studies. In spite of not reaching the original enrollment goal of 20, our findings nonetheless support the continued clinical translation of GSE as an anti-neoplastic and chemopreventive agent against lung cancer.