Neuropathic pain is defined as pain induced by a lesion or disease of the somatosensory nervous system. Pharmacological and non-pharmacological treatments are frequently employed. In the current clinical investigation, we assessed the effects of sex on the safety and effectiveness of medications used to treat neuropathic pain. We conducted a prospective analysis between 1 February 2021 and 20 April 2024, involving patients with neuropathic pain referred to the Ambulatory of Pain Medicine of "Renato Dulbecco" University Hospital in Catanzaro (Calabria, Italy). Patients over 18 years old with signs of neuropathic pain (Douleur Neuropathique en 4 questionnaire ≥ 4) were included. Exclusion criteria comprised patients with Alzheimer's disease; patients with nociplastic or nociceptive pain; and patients with neoplasms. Patients with fewer than two accesses to ambulatory care were excluded, as were those who did not sign the informed consent. Clinical data were collected from each enrolled patient and subsequently analyzed, considering clinical outcomes. Sex and gender differences in efficacy were estimated using multivariate linear modeling and propensity-score matching. During the study, 531 patients were screened, and 174 were enrolled (33.5%, mean age 61.5 ± 13.1; 64 males and 110 females, mean age 60.6 ± 13.4 and 61.96 ± 13.0) in accordance with the inclusion and exclusion criteria. Only minor differences in treatment prescription were observed based on age, body mass index, and comorbidities. Smoking, sex, educational level, and body mass index did not induce a significant change in pain perception. Males required slightly higher, though not significantly, doses of drugs for pain control than females. The treatment was not significantly more effective for females than for males. Females did not exhibit a significantly lower number of adverse drug reactions compared to males. The current study found that there are no appreciable differences between the sexes when it comes to the treatment of neuropathic pain.