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Background: Emerging evidence suggests a possible association between hyperglycaemia and use of dolutegravir, a preferred first-line antiretroviral agent in sub-Saharan Africa. Rigorous studies are needed to validate this association in the light of increasing dolutegravir use and burden of non-communicable diseases among people living with HIV. Methods: We conducted a case-control study in Kampala, Uganda to assess the risk of hyperglycaemia associated with dolutegravir-based antiretroviral therapy (ART). Cases were people living with HIV with hyperglycaemia and controls were people living with HIV without hyperglycaemia, confirmed by fasting plasma glucose and 2-hour oral glucose tolerance tests. Data were collected by interviewer-administered questionnaires and medical record abstraction. Analysis compared cases and controls on dolutegravir use before diagnosis of hyperglycaemia while controlling for potential confounders through multivariable logistic regression. Findings: A total 435 participants were included (204 cases, 231 controls). At bivariate analysis, significant differences in age, education, current body-mass index, hypertension as a comorbidity, previous ART regimen, and current ART regimen existed between cases and controls. Among the 204 cases, 54 (27%) had hyperglycaemic levels that were diagnostic of prediabetes, with 150 (74%) being diagnostic of diabetes. Of note, 75 (40%) participants previously treated with dolutegravir changed to other ART regimens after being diagnosed with hyperglycaemia. In multivariable analysis, patients with previous dolutegravir use had nearly 30-times greater odds of hyperglycaemia compared with those who had non-dolutegravir based regimens (adjusted odds ratio [aOR] 29·06 [95% CI 9·86–85·70]). The odds of hyperglycaemia also increased with age (56 years and older vs 18–35 years, aOR 7·53 [95% CI 2·65–21·38]), and hypertension (aOR 5·64 [2·60–12·21]). Interpretation: Our study shows a strong association between previous dolutegravir exposure and hyperglycaemia. Given the benefits of dolutegravir, its wide-scale roll-out in sub-Saharan Africa, and the growing burden of diabetes, systematic screening of hyperglycaemia before initiation of dolutegravir, routine glucose monitoring, and the consideration of alternate regimens for those at risk for diabetes are needed. Funding: This research was supported by the US National Institutes of Health, Fogarty International Center and Global Health Equity Scholars (grant D43TW010540).