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BACKGROUND: Although WHO recommends starting antiretroviral treatment at a CD4 count of 350 cells/-L, many Ugandan districts still struggle with large proportions of clients initiating ART very late at CD4 less than 50 cells/-L. This study seeks to establish crucial risk factors for very late ART initiation in eastern Uganda. METHODS: All adult HIV-infected clients on ART in Iganga who enrolled between 2005 and 2009 were eligible for this case-control study. Clients who started ART at CD4 cell count of less than 50 cells/-L (very late initiators) were classified as cases and 50-200 cells/-L (late initiators) as control subjects. A total of 152 cases and 202 controls were interviewed. Multivariate analyses were performed to calculate adjusted odds ratios and 95% confidence intervals. RESULTS: Reported health system-related factors associated with very late ART initiation were stock-outs of antiretroviral drugs stock-outs (affecting 70% of the cases and none of the controls), competition from traditional/spiritual healers (AOR 7.8, 95 CI% 3.7-16.4), and lack of pre-ARV care (AOR 4.6, 95 CI% 2.3-9.3). Men were 60% more likely and subsistence farmers six times more likely (AOR 6.3, 95CI% 3.1-13.0) to initiate ART very late. Lack of family support tripled the risk of initiating ART very late (AOR 3.3, 95CI %1.6-6.6). CONCLUSION: Policy makers should prevent ARV stock-outs though effective ARV procurement and supply chain management. New HIV clients should seek pre-ARV care for routine monitoring and determination of ART eligibility. ART services should be more affordable, accessible and user-friendly to make them more attractive than traditional healers