Background: Therapeutic drug monitoring (TDM) guidance suggests that lopinavir trough concentration < 1 or < 3 mcg/mL may be associated with virologic failure. The aim of this analysis was to evaluate the association between lopinavir exposure and virologic response in antiretroviral-naïve subjects. Methods: Data from previously antiretroviral-naïve subjects enrolled in 5 clinical trials of lopinavir/ritonavir (administered BID or QD) plus 2 NRTIs were utilized. Plasma HIV-1 RNA and lopinavir trough concentrations were collected simultaneously at multiple post-baseline visits. Lopinavir exposure and virologic response relationship were analyzed. Results: At Week 48, the suppression rates were similar between subjects with concentration below or above TDM cutoff values. Similar results were obtained when subjects who received lopinavir/ritonavir QD were evaluated separately. In the exposure-response models, there was no significant association between lopinavir trough concentration and virologic response. Conclusions: Trough lopinavir concentrations did not predict the virologic outcome in 856 antiretroviral-naïve subjects treated with lopinavir/ritonavir plus 2 NRTIs. No threshold value for trough lopinavir concentration which resulted in a suboptimal response was identified raising question as to the clinical utility of therapeutic drug monitoring to assess virologic response to lopinavir/ritonavir based therapy in patients on an initial antiretroviral drug regimen.