BACKGROUND: No specific (only subgroup) recommendations for the use of long-acting muscarinic antagonists in chronic obstructive pulmonary disease (COPD) exist. The aim of this exploratory hypothesis generating study was to assess whether different phenotypic/endotypic characteristics could be determinants of the short-term ineffectiveness of the initial tiotropium bromide monotherapy in treatment naïve moderate to severe COPD patients. METHODS: A total of 51 consecutively recruited COPD patients were followed for 3 months after the initial evaluation and prescribed initial treatment (tiotropium). Short-term treatment ineffectiveness was assessed as a composite measure comprising COPD exacerbations, need for additional treatment, and no improvement in functional parameters, e.g. 6‑min walking test (6MWT), body-mass index, airflow obstruction, dyspnea, and exercise (BODE) index and forced expiratory volume in 1 s (FEV1), and as single components. RESULTS: Treatment ineffectiveness was significantly associated with baseline hemoglobin level, COPD assessment test (CAT) score, modified Medical Research Council (mMRC) scale and BODE index (p = 0.002). Incident exacerbation during the follow-up was associated with baseline bronchoalveolar lavage fluid (BALF) alpha-amylase level and CAT score (p < 0.001), and change in treatment with leukocyte count, 6MWT desaturation and fatigue (p < 0.001). No improvement in 6MWT was associated with baseline CAT score, body mass index, mMRC, fatigue, 6MWT and BODE index (p = 0.002). No improvement in BODE index was associated with leukocyte count, serum interleukin 8 (IL-8) and BALF albumin levels (p < 0.001); and no improvement in FEV1 with CAT score, baseline vital capacity and BALF tumor necrosis factor alpha (TNF-alpha) level (p < 0.001). CONCLUSION: Our results suggest that there is a possibility to identify predictors of short-term tiotropium ineffectiveness in patients with moderate to severe COPD.