Introduction: Renal vasculature is extremely sensitive to vasoconstrictor effects of endothelin (ET), while nitric oxide (NO) has special role in several pathological renal conditions. Aim: The aim of this study to examine the presence, character, and degree of changes in NO and ET levels in the serum of extracorporeal shock wave lithotripsy (ESWL)-treated patients with nephrolithiasis. Patients and Methods: This study included a total of 60 patients that were divided in two groups: Group I (n = 24), in which a total of 2000SWs were administered; 0–2 units; (0.5 units per each 500SWs), and Group II (n = 36), in which a total of 4000SWs were administered; 0–4 units; (0.5 units per each 500SWs). Results: In the Group I median NO serum concentration increased in relation to pretreatment levels (39.04 ± 8.29 μmol/L) specifically 30 min, 60 min, and 24 h following the treatment (39.11 ± 12.60), (41.80 ± 6.89), and (46.33 ± 9.03), where concentration growth after 24 h was statistically significant P < 0.01. The NO serum concentration in the Group II increased in relation to pretreatment levels (38.90 ± 10.33 μmol/L) after 30 min (48.71 ± 30.09), 60 min (54.57 ± 39.76), and 24 h (97.95 ± 72.07). The NO concentration increase after 60 min and 24 h is statistically significant, respectively, P < 0.03 and P < 0.0001. Conclusion : NO and ET serum levels are changing under the influence of ESWL, and that the NO and ET changes are directly correlated with the number of administered shock waves and administered energy.