Objective: To compare the outcomes of percutaneous nephrolithotomy (PCNL) in immunocompromised patients with those of PCNL in healthy population. Patients and Methods: A matched case-control study was performed from January 2009 through December 2014 using our prospectively collected kidney stone database. Patients with positive serology to human immunodeficiency virus (HIV), hepatitis C (cellular immune dysfunction), and patients on high dose of immunosuppressive drugs for treatment of autoimmune diseases composed the case group. Control group included patients with kidney stones and no other comorbidity. Patients were randomly matched based on Guy's score as a surrogate of case complexity. Results: Sixty-two patients were enrolled in this study, 21 cases and 42 controls. There were no significant differences in age, gender, and body mass index between groups. Regarding PCNL technique, there were no differences in patient positioning, number of accesses, and operative time. Complication rate was higher in the case group (38.1% vs 14.3%; p = 0.032); however, major complications, defined by Clavien score >= 3, were not statistically different (4.8% vs 2.4%; p = 0.611). There was a tendency of more postoperative urinary tract infection in the case group (19% vs 4.8%; p = 0.069). Mean decrease in hemoglobin level (3.3 vs 2.4 mg/dL; p = 0.037) and blood transfusion rate (23.8% vs 4.8%; p = 0.036) was significantly higher in the case group. Immunocompromised patients had a 2.8-fold increased risk of complications (odds ratio [OR] = 2.0, 95% confidence interval [CI] 1.01, 7.74) and a 5.8-fold increased risk of blood transfusion (OR = 5.8, 95% CI 1.29, 26.55). There were no differences in stone-free rate, nephrostomy tube time, and length of hospital stay. Conclusion: Immunocompromised patients are at higher risk for complications such as bleeding after PCNL.