Abstract Background Comorbidities and adherence to inhaled therapy appears to have a major impact on treatment goals, health status and disease control in chronic obstructive pulmonary disease (COPD). Aim of the study was to assess levels of adherence to inhalers, comorbidities and associations with COPD outcomes in patients residing in rural and semi-urban areas of Greece. Methods Two hundred fifty-seven COPD patients were enrolled from primary health care in 2015–2016. Physicians used structured interviews and questionnaires to assess quality of life and disease status. Patients were classified into groups according to GOLD 2019 guidelines (based on CAT and mMRC). Adherence to inhalers was measured with the Test of Adherence to Inhalers (TAI). Multivariate linear and logistics regression models were used to assess associations between comorbidities and adherence to inhalers with COPD outcomes, including CAT and mMRC scores, exacerbations and GOLD A-D status. Results 74.1% of COPD patients reported poor adherence, while most of them were characterized as deliberate non-compliers (69.5%). 77.1% had ≥2 comorbidities, with overweight/obese (82.2%), hypertension (72.9%) and diabetes mellitus (58%) being the most prevalent. In multivariate analysis, COPD outcomes having significant associations with poor adherence included worse health status [OR (95% CI) 4.86 (1.61–14.69) and 2.93 (1.51–5.71) based on CAT and mMRC, respectively], having ≥2 exacerbations in the past year [4.68 (1.51–4.44)], and disease status e.g., be in groups C or D [3.13 (1.49–8.53) and 3.35 (1.24–9.09) based on CAT and mMRC, respectively). Subjects with gastroesophageal reflux showed better inhaler adherence [OR (95% CI) 0.17 (0.6–0.45)], but none of the comorbid conditions was associated with COPD outcomes after adjustments. Conclusions Poor adherence to inhalers and comorbidities are both prevalent in COPD patients of primary care residing in rural/semi-urban areas of Greece, with adherence influencing COPD outcomes. Raising awareness of patients and physicians on the importance of comorbidities control and inhaler adherence may lead to interventions and improve outcomes.