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Introduction The province of Saskatchewan has the highest incidence of HIV in Canada, and high AIDS-related morbidity and mortality. The HIV infected population in Saskatchewan is unique in Canada because the majority of cases are among individuals of First Nations and Metis ethnicity, the proportion of women who are infected is significantly greater than in other areas of the country, and the most commonly reported exposure is injection drug user (IDU). The highest proportion of cases occur in Saskatoon. Objectives The objectives of this study were (1) to identify factors associated with trends in CD4 count and (2) to identify characteristics of individuals exhibiting faster and slower rates of CD4 cell decline. Methods This is a retrospective longitudinal study from a medical chart review at the Positive Living Program and the Westside Community Clinic in Saskatoon. Inclusion criteria was HIV diagnosis between 1 January 2003 and 30 November 2011, and 18 years of age at time of diagnosis. Results Mean follow-up time for the 457 eligible patients was 46.3 (SD±26.8) months. 254 (53.6%) were male, average age at diagnosis was 35.6 (SD±10.14) years, and 279 (61.1%) were First Nations or Metis. Average baseline log viral load and CD4 count were 4.4 (SD±0.96) and 377.7 cells/mm 3 (SD±232.9), respectively. 340 (74.4%) were Hepatitis C virus (HCV) coinfected, 333 (72.9%) had a history of IDU and 143 (31.1%) were infected with a sexually transmitted infection (STI). 279 (61.1%) patients were recipients of antiretroviral therapy (ARV) during follow-up. 197 (43.1%) were diagnosed with AIDS, either clinical or immunological. 33 (7.2%) were deceased from any cause. Due to high colinearity between First Nations or Metis ethnicity, HCV-coinfection and IDU, three separate multivariate mixed effects models were built. In the first model, First Nations or Metis ethnicity (p=0.028), receipt of ARV (p Conclusions First Nations or Metis ethnicity, HCV coinfection, history of IDU, receipt of social assistance and ARV were identified as factors associated with a more rapid CD4 decline. Individuals exhibiting such factors might benefit from more frequent follow-up by clinicians and earlier initiation of ARV.