To investigate the efficacy and tolerability of using lopinavir/ritonavir concurrently with a third protease inhibitor (PI), the authors reviewed the medical records of 47 HIV-infected patients treated with antiretroviral regimens containing lopinavir/ritonavir and amprenavir, saquinavir, indinavir, or nelfinavir. The baseline mean HIV RNA level was 4.6 log(10) copies/mL, and the median CD4 cell count was 123/mm3. By week 40, one patient (2%) was lost to follow-up, and 21 (44%) discontinued their lopinavir/ritonavir plus a third PI regimens: 4 (8%) due to virologic failure as determined by the clinician; 13 (28%) due to toxicity; and 4 (8%) due to social reasons. By intent-to-treat analysis, 12 (26%) of 47 patients had an HIV RNA level of less than 400 copies/mL at 40 weeks. By multivariate analysis, factors associated with virologic response were no prior lopinavir exposure (p =.03) and no prior exposure to nonnucleoside reverse transcriptase inhibitors among patients taking a nonnucleoside reverse transcriptase inhibitor (p =.05). Some HIV-infected patients concurrently treated with lopinavir/ritonavir and a third PI have viral suppression; many eventually discontinue therapy because of toxicity or virologic failure.