Objectives: To evaluate the efficacy and adverse events (AE) of flexibly adding on oxybutynin ER in patients with overactive bladder (OAB) refractory to monotherapy with the first muscarinic antagonist. Methods: A total of 129 patients with refractory OAB were enrolled in a prospective, open-label protocol. Inclusion criteria were persistent symptoms or partial response to 3-month behavioral therapy and an optimized dose of one antimuscarinic agent. At baseline, weeks 4, and 12 after the oxybutynin ER (5-15mg once a day) was flexibly added, we assessed the OAB symptom indexes and Patient Perception of Bladder Condition, uroflowmetry, and post-void residual, along with the therapeutic effect, AE, and tolerability. Patients continuing combined antimuscarinic therapy were followed up to 12months. Results: Compared with baseline, all OAB symptom indexes significantly decreased at all visits. A total of 32 (24.8%) and 25 (19.4%) patients reported successful therapeutic effect at weeks 4 and 12, respectively. Twenty-four (18.6%) and 44 (34.1%) patients discontinued therapy at weeks 4 and 12, respectively. Only 31 (24.0%) patients continued the combined medication for up to 12months. Discontinuation of the combined medication was noted in 28 (21.7%) patients due to AE and in 70 (54.3%) due to lack of efficacy. Conclusions: Flexibly adding on a second antimuscarinic agent is effective and safe for only some OAB patients dissatisfied with the first antimuscarinic treatment in the short-term period. The patients' dropout rate is high and the long-term efficacy of the combination of two antimuscarinic agents is limited.