Rifampicin induces the metabolism of many drugs. To overcome the reduction in serum concentrations of lopinavir/ritonavir (LPV/r) when used in combination with rifampicin, 800/200 mg or 400/400 mg doses are used. This study evaluated super-boosted LPV/r (400/400 mg) in HIV/TB co-infected patients for adequate concentrations as well as short-term safety, tolerability and clinical response to therapy. This was an open-label, non-randomised pharmacokinetic (PK) study in HIV/TB patients. The primary objective was to determine the PK profile of super-boosted LPV/r when given with a rifampicin-based TB regimen. Secondary objectives were short-term safety, tolerability and clinical response. Primary endpoints were a lopinavir trough concentration (Cmin) >1.0 µg/mL and a rifampicin maximum concentration (Cmax) of 8-24 µg/mL. Secondary PK endpoints were a rifampicin area under the concentration-time curve from 0-24 h (AUC0-24) of 44-70 µg·h/mL, a lopinavir Cmax of 6-14 µg/mL and a lopinavir AUC0-12 of 56-130 µg·h/mL. Eleven patients (10 male, age 25-43 years) were enrolled. Two patients were discontinued due to non-compliance. A lopinavir Cmin of >1.0 µg/mL was achieved in a least one of the PK samplings in all nine subjects who completed treatment. All patients met lopinavir Cmax and AUC0-12 targets. Five patients achieved the primary endpoint of rifampicin Cmax (≥8 µg/mL) in at least one of the PK samplings, and five achieved the minimum rifampicin AUC0-24 (≥44 µg·h/mL). One grade 3 adverse event was reported. Super-boosted LPV/r was safe and effective in HIV/TB patients. [ClinicalTrials.gov ID NCT01700790.].