Treatments administered to patients with chronic obstructive pulmonary disease (COPD), especially when used in multiple combinations, are not free of interactions and side effects that can potentially impair health-related quality of life (HRQL). We studied HRQL and its relationship with treatment in a group of 441 patients with stage II or III COPD (age: 66.6 (SD: 8.3) years; FEV1: 32.4% (SD: 8.1%)) using the St George's Respiratory Questionnaire (SGRQ) and the 12-item short form (SF-12) Health Survey. The most prescribed drugs were ipratropium bromide (87.5%), inhaled corticosteroids (69.4%) and short-acting beta-2 agonists (64.9%). Patients with stage III of the disease were receiving more drugs, particularly short-acting beta-2 agonists (p = 0.002) and inhaled corticosteroids (p = 0.031). The use of theophyllines was associated with a worse total SGRQ score (beta = 4.49; p < 0.001), although this negative association decreased with advanced age. A trend towards worse SGRQ scores was observed with the use of high doses of long-acting beta-2 agonists (beta = 3.22; p = 0.072). Patients receiving three drugs or more presented worse total SGRQ scores than patients receiving fewer drugs (beta = 6.1, p < 0.001; and beta = 7.64, p < 0.001, respectively). These findings suggest that the use of multiple drugs in the treatment of patients with COPD is associated with worse total SGRQ scores. The effect of drugs, their dosages and associations with other drugs on HRQL merit further research.