Because a case report and theoretical mass balances suggested that hypoxic guard systems may not prevent the formation of hypoxic inspired mixtures (FIO2 a parts per thousand currency sign 21 %) over the clinically used fresh gas flow (FGF) range, we measured FIO2 over a wide range of hypoxic guard limits for O-2/N2O and O-2/air mixtures. After IRB approval, 16 ASA I-II patients received sevoflurane in either O-2/N2O (n = 8) or O-2/air (n = 8) using a Zeus(A (R)) anesthesia machine in the conventional mode. After using an 8 L/min FGF with FDO2 = 25 % for 10 min, the following hypoxic guard limits were tested for 4 min each, expressed as [total FGF in L/min; FDO2 in %]: [0.3;85], [0.4;65], [0.5;50], [0.7;36], [0.85;30], [1.0;25], [1.25;25], [1.5;25], [2;25], [3;25], [5;25], and [8;25]. In between these [FGF;FDO2] combinations, 8 L/min FGF with 25 % O-2 was used for 4 min to return to the same baseline FIO2 (25 %) before the start of the next combination. This sequence was studied once in each patient receiving O-2/air (n = 8), but twice in each patient who received O-2/N2O (n = 8) to examine the effect of decreasing N2O uptake over time, resulting in three groups: early O-2/N2O, late O-2/N2O, and O-2/air group. The [FGF;FDO2]-FIO2 relationship was examined. The overall [FGF;FDO2]-FIO2 relationship in the three groups was similar. In all 1, 1.25, and 1.5 L/min FGF groups, FIO2 decreased below 21 % in all but one patient; this occurred within 1 min in at least one patient. In the 0.7 L/min O-2/air group and the 3 L/min late O-2/N2O and O-2/air groups, FIO2 decreased below 21 % in one patient. Current hypoxic guard systems do not reliably prevent a hypoxic FIO2 with O-2/N2O and O-2/air mixtures, particularly between 0.7 and 3 L/min.