Background: Several analgesics are in use for pain control in patients with acute pancreatitis. Procaine hydrochloride (procaine) has a long tradition and is recommended by the German Society of Gastroenterology and Metabolic Diseases for pain treatment in patients with acute pancreatitis. There is no controlled trial showing that procaine could be effective for pain treatment. Methods: In an open, randomized, controlled trial, 107 patients (76 male, 31 female; mean age 45 ± 12 years) were included and randomized either to receive procaine (n = 55) or pentazocine (n = 52) for pain relief. Procaine 2 g/ 24 h was administered by continuous intravenous infusion, pentazocine 30 mg was administered every 6 h as a bolus intravenous injection. Pentazocine was additionally administered on demand whenever required in patients of both treatment groups and its total consumption was recorded. Pain scores were assessed twice daily on a visual analogue scale. Results: Patients receiving procaine were significantly more likely to request additional analgesics compared to patients treated with pentazocine alone, 98 vs. 44%, respectively (p < 0.001). Procaine did not reduce the amount of pentazocine required for pain control. The amount of pentazocine given in both groups was not statistically significantly different. Recorded pain scores were significantly lower (p < 0.001) in patients in the pentazocine group during the first 3 days of analgesic treatment. From day 4 on there was no significant difference in pain scores among the two groups. Conclusion: Thus, intravenous procaine treatment is not effective for pain control in patients with acute pancreatitis.