Background: Hansen’s Disease (HD, or Leprosy) is a mycobacterial infection associated with severe nerve damage and physical disfigurement, primarily affecting economically disadvantaged persons. Increased morbidity occurs when patients experience an immunological reaction to this infection prior to, during, or after HD treatment. Our objective was to identify HD patients at risk for such reactions. Methodology: We performed a multivariate retrospective case--control analysis of HD patient risk for reaction (types 1 and 2) among patients reported in Los Angeles County (LAC) (1995–2016). Risk factors included age, gender, report year, birth place, and bacillary classification (paucibacillary vs. multibacillary). Findings: Most of the 78 LAC HD patients identified for this study were male (78.2%, 61), born in Latin America (48.7%, 38) or South East Asia (SE Asia) (41.0%, 32), classified as multibacillary (88.5%, 69), with a median age of 43.5 years (range 18–82 years). Sixty-two HD patients (79.5%) experienced a reaction type: 34 experienced type 1 (43.6%), 34 experienced type 2 (43.6%), 6 experienced multiple types (7.7%). SE Asian born patients were more likely to experience a type 1 reaction (59.4%, aOR = 3.0, CI: 1.2–7.7), whereas Latin American born patients were more likely to experience a type 2 reaction (68.4%, aOR = 11.1, CI: 3.5–35.1). Conclusion: The risk of reaction types among LAC HD patients appears to be correlated with the patient’s birth place, where their exposure likely occurred. Explanations for these differences include different mycobacterial variants circulating geographically, different immune responses of racial-ethnic groups to HD, and genetic associations. Author Summary: Hansen’s Disease is rare in Los Angeles County and primarily occurs among persons who acquired the infection outside of the US. The findings of this 22-year study of 78 Hansen’s patients suggest that the clinical progression of this disease differs by the global region of exposure. Latin American born patients with Hansen’s disease had eleven times the odds of developing a type 2 reaction, which is associated with severe long-term disability, than patients born in SE Asia. Possible explanations for this result include: (1) variations of the mycobacterial strain across the globe or, (2) variations in immunological responses of racial/ethnic groups to this mycobacterium. Both explanations may be the result of this agent being introduced into the Americans much more recently than in Asia. Clinicians should consider a patient’s race/ethnicity background when developing a Hansen’s Disease treatment plan.