Background Hyperhidrosis (HH) is characterized by exaggerated sweating in a specific region due to hyperfunction of the sweat glands. In the late 2000s, we started treating patients with an anticholinergic, oxybutynin, that was not being used until then. Objectives To present, after 12 years of utilizing this medication in our service, the substantial experience obtained with the use of oxybutynin as an initial treatment of HH in a large series of 1,658 patients. Methods We analyzed 1,658 patients treated with oxybutynin for HH from May 2006 to June 2018. The patients were divided into four groups according to the main site of HH: the plantar group, the axillary group, the facial group, and the palmar group. To measure the degree of satisfaction, a quality of life (QoL) questionnaire was used. Results Pre‐treatment QoL was poor or very poor in more than 94% of the cases, and the palmar group had the worst quality of life. After treatment, we observed an improvement in the quality of life in 77% of patients. More than 70% of the patients in all groups present moderate or optimal subjective clinical improvement in sweating after treatment. The group with the best result was the facial group. Intense dry mouth was reported in 24.9% of all patients in all groups. Conclusions This study included a large number of patients followed for a long period and demonstrated the good effectiveness of treatment with oxybutynin for hyperhidrosis in the main sites of sweating.