Objectives: Pain is a common symptom in prehospital emergency care and pain treatment in this context can be challenging. While previous research has assessed the use of morphine and other synthetic opioids for pain management in this setting, the evaluation of alfentanil is limited. The objective of this study was to evaluate the safety and effect of intravenous alfentanil when administered by ambulance nurses in prehospital emergency care. Methods: This retrospective observational study consecutively included patients suffering from pain, treated with alfentanil in a Swedish EMS service from September 2011 to 31 September 2022. Data regarding occurrence of adverse events (AE), serious adverse events (SAE)–were used for safety evaluation and pain scores with a visual analogue scale (VAS) before and after treatment were used for evaluation of pain treatment. These data were extracted from the electronic patients’ medical records database for analysis. Univariate logistic regression analysis was used to identify significant predictors of AE following injection of alfentanil by nurses in prehospital emergency care. Results: During the evaluation period 17,796 patients received pain relief with alfentanil. Adverse events affected 2.5% of the patients, while serious adverse events were identified in 25 cases (0.01%). Out of the 5970 patients with a complete VAS score for pain, the median VAS score was 8 (IQR 3) before treatment and 4 (IQR 3) after treatment. The mean reduction in pain measured by VAS was −4.1 ± 2.6 from the time before, to the evaluation after alfentanil administration. The administration frequency increased during the first year up to a steady level during the later part of the evaluation period. Conclusions: This study proposes that alfentanil represents a safe and efficacious alternative for addressing urgent pain relief within the prehospital emergency context. Alfentanil demonstrates efficacy in alleviating pain across various conditions, with a relatively low risk of adverse events or serious adverse events when administered cautiously.