Oxidation flow reactors (OFRs) are increasingly employed in atmospheric chemistry research because of their high efficiency of OH radical production from low-pressure Hg lamp emissions at both 185 and 254 nm (OFR185) or 254 nm only (OFR254). OFRs have been thought to be limited to studying low-NO chemistry (in which peroxy radicals (RO2) react preferentially with HO2) because NO is very rapidly oxidized by the high concentrations of O3, HO2, and OH in OFRs. However, many groups are performing experiments by aging combustion exhaust with high NO levels or adding NO in the hopes of simulating high-NO chemistry (in which RO2 + NO dominates). This work systematically explores the chemistry in OFRs with high initial NO. Using box modeling, we investigate the interconversion of N-containing species and the uncertainties due to kinetic parameters. Simple initial injection of NO in OFR185 can result in more RO2 reacted with NO than with HO2 and minor non-tropospheric photolysis, but only under a very narrow set of conditions (high water mixing ratio, low UV intensity, low external OH reactivity (OHRext), and initial NO concentration (NOin) of tens to hundreds of ppb) that account for a very small fraction of the input parameter space. These conditions are generally far away from experimental conditions of published OFR studies with high initial NO. In particular, studies of aerosol formation from vehicle emissions in OFRs often used OHRext and NOin several orders of magnitude higher. Due to extremely high OHRext and NOin, some studies may have resulted in substantial non-tropospheric photolysis, strong delay to RO2 chemistry due to peroxynitrate formation, VOC reactions with NO3 dominating over those with OH, and faster reactions of OH–aromatic adducts with NO2 than those with O2, all of which are irrelevant to ambient VOC photooxidation chemistry. Some of the negative effects are the worst for alkene and aromatic precursors. To avoid undesired chemistry, vehicle emissions generally need to be diluted by a factor of > 100 before being injected into an OFR. However, sufficiently diluted vehicle emissions generally do not lead to high-NO chemistry in OFRs but are rather dominated by the low-NO RO2 + HO2 pathway. To ensure high-NO conditions without substantial atmospherically irrelevant chemistry in a more controlled fashion, new techniques are needed.