The aim of our study was to investigate the effect of duloxetine on urethral function and sphincter ultrasound morphology in 54 women, who were referred to a urogynecology unit, with urodynamic stress incontinence. All completed a King's Health Questionnaire and a patient global assessment of improvement (PGI-I) question and underwent urethral pressure profilometry, measurement of urethral retro-resistance pressure (URP), and ultrasound of the striated urethral sphincter. The investigations were repeated after 8 weeks of duloxetine 40 mg twice daily in 36 women who continued the medication. After 8 weeks of duloxetine, the mean URP increased significantly compared to baseline (53.8 to 60.8 cm H2O; p=0.001), and sphincter thickness was significantly higher (1.8 to 2.0 mm; p<0.001). There was a significant increase in the maximum urethral closure pressure (MUCP) (52.7 to 59.2 cm H2O; p=0.006) but not of functional urethral length. Subanalysis of responders (improved on duloxetine) showed a significant increase in URP (50.3 to 59.1 cm H2O; p=0.001), sphincter thickness (1.7 to 2.1 mm; p<0.001), and MUCP (50.2 to 58.1 cm H2O; p=0.03). These changes were not seen in nonresponders. This study has demonstrated objective changes in urethral ultrasound morphology and function after duloxetine therapy, which relate to improved continence. A larger longer term study is required to assess if these changes persist over time. In summary, duloxetine therapy for urodynamic stress incontinence results in an increase in urethral closure pressure, URP measurement, and urethral striated sphincter thickness.