Background In line with its half century old penal code, Ghana currently criminalizes and penalizes behaviors of some key populations – populations deemed to be at higher risk of acquiring or transmitting Human Immunodeficiency Virus (HIV). Men who have sex with men (MSM), and sex workers (SWs) fit into this categorization. This paper provides an analysis of how enactment and implementation of rights-limiting laws not only limit rights, but also amplify risk and vulnerability to HIV in key and general populations. The paper derives from a project that assessed the ethics sensitivity of key documents guiding Ghana’s response to its HIV epidemic. Assessment was guided by leading frameworks from public health ethics, and relevant articles from the international bill of rights. Discussion Ghana’s response to her HIV epidemic does not adequately address the rights and needs of key populations. Even though the national response has achieved some public health successes, palpable efforts to address rights issues remain nascent. Ghana’s guiding documents for HIV response include no advocacy for decriminalization, depenalization or harm reduction approaches for these key populations. The impact of rights-restricting codes on the nation’s HIV epidemic is real: criminalization impedes key populations’ access to HIV prevention and treatment services. Given that they are bridging populations, whatever affects the Ghanaian key populations directly, affects the general population indirectly. Summary The right to the highest attainable standard of health, without qualification, is generally acknowledged as a fundamental human right. Unfortunately, this right currently eludes the Ghanaian SW and MSM. The paper endorses decriminalization as a means of promoting this right. In the face of opposition to decriminalization, the paper proposes specific harm reduction strategies as approaches to promote health and uplift the diminished rights of key populations. Thus the authors call on Ghana to remove impediments to public health services provision to these populations. Doing so will require political will and sufficient planning toward prioritizing HIV prevention, care and treatment programming for key populations.