The objective of this observational cohort study was to compare adherence to protease inhibitor (PI)-based regimens or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. HIV-seropositive, antiretroviral-naïve patients initiating therapy between 1998 and 2006 were identified using Veterans Health Administration databases. First-year adherence ratios were calculated as proportion of days covered (PDC). Multivariable regressions were run with an indicator for PDC >95, 90, 85, and 80 % as the dependent variable and an indicator for a PI-based regimen as the key independent variable. We controlled for residual unmeasured confounding by indication using an instrumental variable technique, using the physician's prescribing preference as the instrument. Out of 929 veterans on PI-based and 747 on NNRTI-based regimens, only 19.7 % of PI patients had PDC >80 %, compared to 35.1 % of NNRTI patients. In multivariable analysis, starting a PI regimen was significantly associated with poor adherence for all 4 adherence thresholds using conventional regressions and instrumental variable methods.