OBJECTIVE: To examine the presence of interleukin-1 (IL-1), interleukin-6 (IL-6), and creatine phosphokinase-MM (CPK-MM) in patients with acute scrotal pain and assess their clinical utility in the diagnosis of testicular torsion (TT) and epididymitis. METHODS: Twenty-five patients with acute scrotal pain were prospectively enrolled over a two-year period. History, physical examination, complete blood count, urinalysis, and scrotal ultrasound were performed. Testicular torsion was confirmed by surgical exploration. Epididymitis was diagnosed using physical examination, scrotal ultrasound, and positive urinalysis. Venous blood was assayed for IL-1, IL-6, and CPK-MM in triplicate during the routine drawing of blood in the emergency department. The data are reported as medians +/- interquartile ranges (IQRs). RESULTS: Twenty-five patients with acute scrotal pain were evaluated; 11 with TT, three with torsion of the appendix testis (TAT), ten with epididymitis, and one with varicocele. One patient had both TT and epididymitis. Interleukin-1 was not detectable in either group. The CPK-MM values between TT and epididymitis were virtually identical at 99.8 and 100 IU/L, respectively. The median value for IL-6 was 1. 03 (IQR = 0.19 to 2.86) vs 20.86 (IQR = 2.14 to 65.50) pg/mL in the torsion and epididymitis groups, respectively. The 97.5% CI for the difference of medians of 19.9 was 0.4 to 65.1, p = 0.02. Using receiver operating characteristic (ROC) curve analysis for IL-6, the area under the curve was 0.82 for torsion and 0.67 for epididymitis. Using a cutoff value of IL-6 >/= 1.41 pg/mL, the positive predictive value of IL-6 in diagnosing epididymitis was 78.6%, with a negative predictive value of 100% for TT. There were no cases of missed TT on follow-up. CONCLUSIONS: This preliminary investigation of serologic markers demonstrates that IL-6 is significantly elevated in epididymitis as compared with TT. Creatine phosphokinase-MM and IL-1 were not found to be of diagnostic utility. The small sample size of this study precludes a definitive conclusion as to the utility of these markers in the emergency department. However, IL-6 may be clinically useful as an additional element in differentiating the causes of acute scrotal pain, and further study is warranted.