Background: Late initiation of treatment for illness secondary to the human immunodeficiency virus (HIV) remains a major challenge in developing countries. Despite the World Health Organization (WHO) recommendation that treatment be initiated early in disease management, health providers conducting quality improvement monitoring in one region of Tanzania noted that common management practice relies upon clinical signs of advanced disease alone for initiation of combination antiretroviral therapy (ART). Although Tanzanian National Treatment Guidelines followed standard WHO recommendations, few patients initiated ART based on laboratory parameters. As a potential barrier to optimal patient outcomes, further investigation of this inconsistency led to recognition of challenges reflecting patient, healthcare staff, and laboratory levels that might inhibit the use of CD4 cell counts as the entryway to care. Materials and Methods: Using a quality improvement approach, investigations were pursued for six discrete activities of HIV care delivery with before and after measures of selected indicators. With respect to patient engagement, meetings and informal educational sessions were held to promote understanding of the meaning of and need for CD4 testing. For clinic staff: (1) Qualitative interviews were conducted with providers to understand why laboratory data was not being used and (2) on-site interviews were conducted with laboratory personnel to review beliefs, methods, and practices related to measurement of CD4 cells testing. A large scale local campaign was mounted to (1) educate and empower patients to recognize a need for CD4 information in management of their own care; (2) re-educate and encourage providers to use measured, rather than clinical observation alone to initiate ART; and (3) understand and resolve clinical and laboratory challenges. Based upon findings from the interviews: (1) Meetings with hospital administrations were effected to resolve institutional barriers to using CD4 cell testing. Specific on-site training was initiated for both providers, with regard to use of CD4 cell counts, and nurses, with advanced training to initiate routine CD4 testing. These activities were well received because all staff were able to review unlinked, site-based clinical data to appreciate gaps in a local care. Results: The number of CD4 samples obtained and recorded increased by 114% between May and October 2007 at targeted health facilities. ART enrollment increased by 62% between June and September 2007 without other significant change in care delivery. The median baseline CD4 at enrollment increased from 110 cells/mm3 in June to 150 cells/mm3 in September. Overall retention rate was 77% for 13,333 HIV patients enrolled in seven facilities. In September 2013, the cumulative 6-year overall retention rates are 77% for 53,040 patients enrolled in 42 health facilities in the region. Obstacles were addressed and community empowerment techniques used to stimulate change in established clinical behaviors. Conclusion: This “Know your CD4 campaign” initiative resulted in increased uptake of CD4 testing, treatment initiation and an unanticipated improvement in patient retention. With attention to patient, staff, and laboratory elements in resource-poor settings, decline in immune function and morbidity may be reduced and viral suppression prolonged. Empowering patients to be involved in their own care resulted in better overall adherence with HIV management. Local use of reviewed data can impact overall effectiveness of HIV care delivery. Simple quality improvement approaches impact sustainable change.