A rapid and sensitive method using liquid chromatography–tandem mass spectrometry (LC–MS/MS) has been developed for the simultaneous determination of telmisartan and hydrochlorothiazide in human plasma. Sample preparation involved liquid–liquid extraction with diethyl ether–dichloromethane (60:40, v/v). The analytes and internal standard, probenecid, were separated on a Venusil XBP-C8 column using gradient elution with acetonitrile–10 mM ammonium acetate–formic acid at a flow rate of 1.2 mL/min. Detection was by electrospray negative ionization mass spectrometry using multiple reaction monitoring of the transitions at m/z 513.0 → 469.4 for telmisartan, m/z 295.9 → 268.9 for hydrochlorothiazide and m/z 283.9 → 239.9 for probenecid. For both analytes, the method was linear in the range 1.00–600 ng/mL with intra- and inter-day precision (as relative standard deviation) ≤10.6% and accuracy (as relative error) ≤4.2%. The assay was successfully applied to a pharmacokinetic study in 9 healthy volunteers given a single oral dose of a combination tablet containing telmisartan 80 mg and hydrochlorothiazide 12.5 mg.