Background Tobacco-associated lung microangiopathy (TALM) is supported by thorax vascular computerized tomography and histopathological studies, and could be associated with effort intolerance and altered muscle oxygen extraction during the exercise. Objectives To characterize symptomatic smokers without chronic obstructive pulmonary disease for TALM, and testing the acute effects of 50 mg of sildenafil on exercise tolerance (Tlim), pulmonary oxygen uptake (time constant ??O2) and vastus lateralis muscle deoxyhemoglobin kinetics [?HHb]. Methods Smokers with (i) dyspnea (Med.Res.Council ? 1), (ii) Tiffeneau index>70%, (iii) lower than the lower limit of normality carbon monoxide transfer factor and difusion coefficient, despite preserved alveolar volume, (iv) emphysema score < 5%, and (v) increased minute ventilation-to-carbon dioxide output (VŽ_E-VŽCO₂ slope) during maximal incremental cardiopulmonary exercise test, were considered suspected for TALM. Additional replicated high-intensity constant work tests under placebo or sildenafil, on a crossover design, were performed and compared through repeated measure ANOVA. Results Sixteen smokers and eight control subjects were enrolled. No differences between groups and treatment for Tlim, ??O2 and [?HHb] were found (p>0.05 for all). There was a significant group vs treatment VŽ_E/VŽCO₂ interaction, showing worst ventilatory efficiency under sildenafil treatment for smokers (p=0.003). Conclusion Despite highly focused clinical-functional and imaginology criteria for TALM definition, sildenafil was not effective in increasing important exercise endpoints.