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The worsening opioid epidemic ignites infectious disease development and transmission as opioids abused by insufflation and/or injection establish a pathway for infection to the user and propagate vulnerability to diseases. The phenomenon of the synergistic collision of epidemics intensifying the load of disease constitutes a syndemic. Merrill Signer (1994) voiced the term “syndemic” to characterize the complex nexus of politics, economics, psychosocial/environmental factors, and health disparities resulting in the inner-city AIDS crisis of the 1990s. Today, the surge of opioid use puts individuals at risk for disease transmission and living the catastrophic clash wrought by the epidemics. By following a case study caught in the crossfire of epidemics, this article prompts to underscore recognition of the at-risk patient for HIV infection and to embolden care integration of prevention and treatment strategies nurses are qualified to execute.