Objective. Determining the etiology of unexplained leukocytosis in asymptomatic patients may incur unnecessary testing, cost, and prolonged emergency department stay. The objective was to delineate if use of amphetamines and/or cocaine is a factor. Methods. For two years we reviewed all psychiatric patients presenting for medical clearance with exclusions for infection, epilepsy, trauma, or other nonpsychiatric medical conditions. Results. With a total of 1,206 patients, 877 (72.7%) amphetamines/cocaine-negative drug screen controls had mean WBC 8.4 ± 2.6 × 103/µL. The 240 (19.9%) amphetamines-positive, cocaine-negative, patients had WBC 9.4 ± 3.3 × 103/µL (P < 0.0001). The 72 (6.0%) amphetamines-negative, cocaine-positive, patients had WBC 7.1 ± 1.8 × 103/µL (P < 0.0001). The remaining 17 (1.4%) amphetamines/cocaine-positive patients had WBC 10.0 ± 4.2 × 103/µL (P = 0.01). Amphetamines-positive patients had a supranormal WBC ratio significantly higher than controls (23.8% versus 14.8%, P = 0.001), whereas only one cocaine-positive patient had a supranormal WBC count, with significantly lower ratio (1.4%, P = 0.0003). Conclusion. Use of amphetamines, not cocaine, may be associated with idiopathic leukocytosis. This may be explained by unique pharmacologic, neuroendocrine, and immunomodulatory differences.