Purpose <p>Vaginal cancer (ICD-10: C52) is one of the rarest gynecological malignancies, with limited research on its frequency, long-term survival, therapy-dependent survival, and follow-up of recurrences. This knowledge deficit may lead to potential consequences such as medical over-, under- or wrong therapy.</p> Methods <p>This nationwide retrospective population-based registry study analyzed patients with vaginal cancer diagnosed between 2000 and 2022 in Germany. A total cohort of 1325 patients was included. To assess prognostic factors related to lymph node involvement, overall survival, recurrence rates, and therapy-dependent survival were analyzed using binary logistic regression, the Kaplan-Meier method, and univariable and multivariable Cox regression.</p> Results <p>Mean age at diagnosis was 68.5 years and median age was 70.4 years. 30.0% (<i>n</i> = 398) of patients showed lymph node involvement. Younger age at diagnosis (&lt; 60 years), larger tumor size, and lymphatic invasion were noted as significant risk factors for lymph node involvement in multivariable analysis. The 5-year overall survival rate was 53.8% (95%-CI 50.9–56.7), significantly influenced by age at diagnosis, nodal status, and tumor size in multivariable analysis. Cumulative recurrence rates for locoregional and distant metastases were 20.4% and 14.3% after 5 years, increasing to 24.3% and 16.5% after 10 years. The most common primary treatment was surgery (39.2%, <i>n</i> = 454). Surgery plus radiochemotherapy (OP + RCT) provided the most favorable outcome as a primary treatment, whereas radiotherapy alone showed the least benefit of all treatment options.</p> Conclusion <p>Our study identifies important prognostic factors influencing vaginal cancer survival and offers information on treatment optimization.</p>