HIV/AIDS and non-communicable diseases (NCDs) epidemics may have many important similarities in their aetiology, pathogenesis and management. Evidence about the similarities and differences between the national responses HIV/AIDS and NCDs is essential for an integrated response. The objective of this study was to examine the parallels and differences between national responses to HIV/AIDS and NCDs in selected developing countries. This study applied a strategic level comparative case study approach as its study design. The main construct was national response to HIV/AIDS and NCDs. The 4 overarching themes were policy response, institutional mechanism, programmatic response and strategic information. Four countries were purposively selected as cases. Data were collected and triangulated from a multiple sources. The focus of analysis included identifying items for comparison, characteristics to be compared, degrees of similarity, and strategic importance of similarities. Analysis of data was qualitative content analysis with within-case, between-case, and across-case comparisons. While the nature of the disease and the contents of national HIV/AIDS and NCD policies are different, the policy processes involved are largely similar. Functional characteristics of programmatic response to HIV/AIDS and NCDs are similar. But the internal constituents are different. Though both HIV and NCDs require both a multi-sectorial response and a national coordination mechanism, the model and the complexity of the coordination are different. Strategic information frameworks for HIV/AIDS and NCDs use similar models. However, the indicators, targets and priorities are different. In conclusion, the national responses between HIV/AIDS and NCDs are largely similar in approaches and functions but different in content.