Antiretroviral treatment (ART) adherence is highlighted in management of patients living with human immunodeficiency virus. In South Korea, ART medication research has rarely been conducted due to the low economic burden associated with government-funded treatment. This cross-sectional study aimed to compare the pill burden impact between ART regimen compliance and HIV-RNA viral load suppression. Data were collected from 2008 to 2016 at a general hospital in South Korea. A total of 210 HIV/AIDS treatment-naïve patients were grouped as follows: single-tablet regimen (STR, one tablet/day), mild pill burden (two-four tablets/day), and heavy pill burden ([greater than or equal to] five tablets/day). Patients were analyzed according to gender, age at index date, medical insurance type, comorbidities, depression, HIV/AIDS disease burden as indicated by HIV-RNA viral load and CD4, and laboratory variables. In a multivariate logistic regression model, the STR group demonstrated adherence 5.10 times more often than the heavy pill burden group. Females and patients with an initial viral load of 500,000 or more were 0.090- and 0.040-fold less adherent to the ART regimen. Among these patients, 95% or more of the MPR group were 7.38 times more likely to have a lower limit of detection (LLOD) of viral load suppression. The highest initial viral load group was 0.090-fold less likely to have an LLOD than the reference group. These results suggest that a single-tablet regimen could improve medication adherence and the clinical virologic outcome. Therefore, general population research on ART adherence and polypharmacy is needed.