Introduction and Hypothesis <p>Intrasphincteric injection of autologous skeletal muscle-derived cells (aSMDCs) is a minimally invasive treatment for stress urinary incontinence (SUI). This study investigated two cell counts (high/low dose) for functional urethral sphincter regeneration in combination with electrical stimulation, treatment safety and efficacy, and its potential superiority to duloxetine-placebo or duloxetine.</p> Methods <p>This phase II, placebo-controlled trial randomised women with SUI to cell implantation (low or high cell number) and to control groups (duloxetine-placebo or duloxetine), each treatment combined with electrical stimulation. The primary efficacy endpoint was the mean reduction of incontinence episode frequency (IEF) at 12&#xa0;weeks post-treatment compared with baseline. Secondary efficacy parameters included 1-h pad test, visual analogue scale (VAS), Incontinence Quality of Life questionnaire, clinical global impression score and frequency of responders based on IEF. Adverse events were analysed for safety evaluation. Additional follow-up data on IEF and selected secondary efficacy variables were obtained in a sub-population of patients after 12 and 48 months.</p> Results <p>The mean reduction ± SD in IEF after 12&#xa0;weeks was: low cells: −16.4 ± 13.3 (61 patients), high cells: −18.5 ± 18.7 (56), placebo: −9.7 ± 13.7 (68), duloxetine −11.2 ± 19.6 (32). Cell treatments were significantly superior over placebo regarding IEF reduction and all secondary endpoints except for VAS. No safety issues were observed following cell implantation. Improvements were sustained over 12 and 48&#xa0;months, with no difference between low and high cell implantation groups.</p> Conclusions <p>Therapy for SUI with aSMDCs in combination with electrical stimulation is safe, effective and sustained over at least 48&#xa0;months.</p>