Introduction: Despite proven effectiveness of medications in preventing stone recurrence, compliance with pharmacotherapy (PT) is often poor because of cost, side effects, and impact on lifestyle. We sought to compare the risk of stone recurrence between patients managed with conservative therapy (CT) vs PT controlling for aggressiveness of stone disease. Materials and Methods: The Multi-center collaboration to Study Treatment Outcomes in Nephrolithiasis Evaluation (MSTONE) database contains patient data and outcomes from July 2001 to April 2015 across four centers. The database was queried for patients whose stone disease was managed with CT alone (fluid and dietary recommendations) vs PT. Patients were risk stratified according to number of previous passed stones. Within each risk group, we compared CT vs PT with respect to 2-year stone event rate and stone event-free survival (SEFS) using the Kaplan-Meier method. Results: A total of 245 patients, with a median follow-up of 29 months (interquartile range = 16-44), were identified, including 93 on CT and 152 on PT. The overall 2-year stone event rate was 38% for all patients. Stone events at 2 years occurred less frequently in the PT group compared with the CT group (31% vs 44%, p = 0.043), with the difference most pronounced in the high-risk group (71% vs 32% for CT and PT, respectively, p = 0.058). The 30-month SEFS was significantly higher for PT (58%) than CT (46%) overall. When stratified by risk group, 30-month SEFS was statistically significantly higher for PT than CT in the intermediate risk group (65% vs 45% for PT and CT, respectively). Conclusion: Controlling for aggressiveness of stone disease, PT was more effective than CT in reducing and delaying stone-related events. However, CT appeared to be as effective as PT in low-risk patients. PT is best reserved for recurrent stone formers, regardless of metabolic background.