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The present study sought to describe the use of generic drugs and single-tablet regimen (STR) de-simplification for the treatment of human immunodeficiency virus (HIV) infection among 41 hospitals from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). In June 2018, we collected information on when generic antiretroviral drugs (ARVs) were introduced in the different hospitals, how the decisions to use them were made, and how the information was provided to the patients. Most of the nine available generic ARVs in Spain by June 2018 had been introduced in at least 85% of the participating hospitals, except for zidovudine (AZT)/lamivudine (3TC) and AZT. The time difference between the effective marketing date of each generic ARV and its first dispensing date in the hospitals was much shorter for the more recently approved generic ARV since the year 2017. However, only up to 20% of the hospitals de-simplified efavirenz (EFV)/tenofovir disoproxil (TDF)/emtricitabine (FTC), dolutegravir (DTG)/abacavir (ABC)/3TC, and rilpivirine (RPV)/TDF/FTC (to generic EFV+TDF/FTC, DTG+generic ABC/3TC, and RPV+generic TDF/FTC, respectively), whereas the generic STR EFV/TDF/FTC was introduced in 87.8% of the centers. The median times between the date of effective marketing of generic TDF/FTC and the date of de-simplification of EFV/TDF/FTC and RPV/TDF/FTC were 723 [interquartile range (IQR): 369–1,119] and 234 (IQR: 142–264) days, respectively; this time was 155 (IQR: 28–287) days for de-simplification of DTG/ABC/3TC. In conclusion, despite the widespread use of generic ARVs, STRs de-simplification was only undertaken in <20% of the hospitals. There was wide variability in the timing of the introduction of each generic ARV after they were available in the market. [ABSTRACT FROM AUTHOR]