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Background New antiretroviral (ARV) drugs and improved formulations and coformulations of existing ARVs are actively promoted to diminish a patient's pill burden and to minimise the opportunity for mismatched dosing, although the effect of these advances is poorly understood. We determine how these changes affect the total daily pill burden (TDPB) for ARV and other drug use over a 20-year period. Methods Using our in-house pharmacy database, we calculated the daily number and associated pill burden of oral ARV and non-ARV (prescription and over-the-counter) medications taken by every patient within the Southern Alberta Cohort (SAC) between 1990 and 2010. We compared the mean TDPB with the patients’ sociodemographic and clinical characteristics. Results Mean TDPB for ARV-experienced patients increased from 4.9 in 1990 to 12.1 in 1998 but decreased to 6.7 in 2010. By 2010, new ARVs and newer formulations had decreased ARV pill burden by 50% over five years. In 1990, however, 95% of the TDPB consisted of ARVs but by 2010 it fell to 51% as non-ARV daily drugs increased from 0.2 in 1990 to 2.6 in 2010. Variation in TDPB was attributable to four main factors: patient's age, risk factor, nadir CD4 + T-cell count and duration of known HIV infection. Conclusions While new ARV formulations and coformulations have simplified regimens, this reduction in ARV pill burden has been counterbalanced by increases in non-ARV drugs required for managing comorbidities. Discussions on merits of coformulations in decreasing ARV pill burden need to include the non-ARV pill burden.