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Introduction Although the prevalence of chronic obstructive pulmonary disease (COPD) is similar between men and women, current evidence used to support bronchodilator therapy has been generated in therapeutic trials that have predominately enrolled male patients. Here, we determined whether there is any significant sex-related differences in FEV1 responses to ipratropium bromide. Methods Data from the Lung Health Study (n = 5887; 37% females) were used to determine changes in FEV1 with ipratropium or placebo in male and female subjects with mild to moderate COPD over 5 years. Lung Expression Quantitative Trait Loci (eQTL) dataset was used to determine whether there were any sex-related differences in gene expression for muscarinic (M2 and M3) receptors in lungs of male and female patients. Results After 4 months, ipratropium therapy increased FEV1 by 6.0% in female and 2.9% in male subjects from baseline values (p = 2.42 × 10− 16). This effect was modified by body mass index (BMI) such that the biggest improvements in FEV1 with ipratropium were observed in thin female subjects (p for BMI ∗ sex interaction = 0.044). The sex-related changes in FEV1 related to ipratropium persisted for 2 years (p = 0.0134). Female compared with male lungs had greater gene expression for M3 relative to M2 receptors (p = 6.86 × 10− 8). Conclusion Ipratropium induces a larger bronchodilator response in female than in male patients and the benefits are particularly notable in non-obese females. Female lungs have greater gene expression for the M3 muscarinic receptor relative to M2 receptors than male lungs. Female patients are thus more likely to benefit from ipratropium than male COPD patients., Highlights • Ipratropium; a muscarinic antagonist bronchodilator is more effective in female COPD patients compared to males. • The effect was modified by body mass index (BMI) such that thin female subjects respond better. • Female compared with male lungs had greater gene expression for the M3/M2 ratio of muscarinic receptors. Most evidence used to support bronchodilator therapy in COPD has been generated in therapeutic trials with predominately male patients. Here, we determined whether there are any significant sex-related differences in lung function responses to the bronchodilator ipratropium bromide. After 4 months, ipratropium therapy increased lung function in females twice as much as males. This effect was modified by body mass index (BMI) such that the biggest improvements in lung function with ipratropium were observed in thin female subjects. Female compared with male lungs had greater gene expression for ipratropium receptors. Female patients are likely to benefit more from ipratropium than male COPD patients.