Background: Premature ejaculation (PE) is a common sexual dysfunction in men, impacting relationships and quality of life. Current treatments include selective serotonin reuptake inhibitors (SSRIs) and opioid receptor agonists, but their comparative efficacy is not well-established. Objective: To compare the efficacy of tramadol (an opioid receptor agonist) with paroxetine (an SSRI) in the treatment of PE. Methods: This randomized control trial was conducted at Jinnah Postgraduate Medical Center, Karachi, from October 2020 to April 2021. Male patients aged 18-55 years, diagnosed with PE, were included. Exclusion criteria were erectile dysfunction, substance abuse, psychiatric illnesses, and ongoing PE treatment. Participants were divided into two groups: one receiving tramadol and the other paroxetine, taken 2-4 hours before intercourse. Efficacy was measured using Intravaginal Ejaculation Latency Time (IELT) over a six-week period. Data were analyzed using SPSS version 21, with a p-value of <0.05 considered significant. Results: 200 participants were included, with 100 in each treatment group. Tramadol showed a higher efficacy (89% efficacy) compared to paroxetine (73% efficacy), with a significant p-value of 0.004. Stratified analyses by age, BMI, and duration of relationship also indicated higher efficacy for tramadol across different subgroups. Conclusion: Tramadol demonstrated superior efficacy in delaying ejaculation compared to paroxetine in the treatment of PE. These findings suggest that tramadol may be a more effective alternative for PE management, although further research is needed to confirm these results and explore long-term outcomes.