Xpert MTB/RIF (Xpert) offers rapid detection of Mycobacterium tuberculosis and rifampicin resistance. However, little is known about routine point-of-care (POC) use in high TB/HIV burden settings. We describe our experiences of launching Xpert as the POC, initial diagnostic for all TB suspects at a primary healthcare clinic in Johannesburg, South Africa. Noted important benefits of POC Xpert were fewer clinic visits, rapid detection of TB and rifampicin resistance, real-time assessment of accompanying household members of new TB cases, and increased staff motivation for TB screening. While Xpert results are available within 2 hours, actual turn-around time was longer for most patients because of sample preparation time and clinic congestion. Consequently, a GX4 instrument did not result in a 16-test capacity during an 8-hour working day, and some patients did not receive same-day results. Loss to follow-up was an unforeseen challenge, overcome by clinic flow changes, marking of clinic files, documenting patients' physical description and locating patients in the clinic by cell phone. Staff with high school education successfully performed the assay after minimal training. Human resource requirements were considerable, with a minimum of 2 staff needed to supervise sputum collection, process sputum, perform assays, and document results for an average of 15 TB suspects daily. POC placement of the instrument transferred logistical responsibilities to the clinic, including quality assurance, maintenance, stock control and cartridge disposal. POC use of Xpert is feasible at the primary healthcare level but must be accompanied by financial, operational and logistical support.