An accurate, selective, and sensitive method for the determination of the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine (nvp) and efavirenz (efv) in human plasma using gas chromatography-mass spectroscopy in selected ion monitoring mode (GC/MS-SIM) was developed. Solid-phase extraction (SPE) gave extraction yields near 100% for both nvp and efv, and calibration curves were linear over the therapeutic concentration ranges. Variation of intraday and interday precision was below 5%. Intraday and interday inaccuracies varied between 0.6% and 10.4%. The lower limits of detection using a 200-μL plasma sample were 27 ng/mL for nvp and 26 ng/mL for efv, and the lower limits of quantification were 54 ng/mL and 72 ng/mL, respectively. The method was applied to the determination of nvp and efv in plasma specimens of 73 patients in HIV stage III or IV and on antiretroviral treatment in Kigali, Rwanda.