In the oil and gas industry, large variations in flow rates are often encountered, which require compression trains with a wide operating range. If the stable operating range at constant speed is insufficient, variable speed drivers can be used to meet the requirements. Alternatively, variable inlet guide vanes (IGVs) can be introduced into the inlet plenum to provide pre- or counterswirl to the first-stage impeller, possibly eliminating the need for variable speed. This paper presents the development and validation of circumferentially nonuniform IGVs that were specifically designed to provide maximum angle variation at minimum losses and flow distortion for the downstream impeller. This includes the comparison of three concepts: a baseline design based on circumferentially uniform and symmetric profiles, two circumferentially nonuniform concepts based on uniquely cambered airfoils at each circumferential position, and a multi-airfoil configuration consisting of a uniquely cambered fixed part and a movable part. The idea behind the circumferentially nonuniform designs was to take into account nonsymmetric flow features inside the plenum and a bias toward large preswirl angles rather than counter-swirl during practical operation. The designs were carried out by computational fluid dynamics (CFD) and first tested in a steady, full-annulus cascade in order to quantify pressure losses and flow quality at the inlet to the impeller at different IGV setting angles (ranging from −20 deg to +60 deg) and flow rates. Subsequently, the designs were mounted in front of a typical oil and gas impeller on a high-speed rotating rig in order to determine the impact of flow distortion on the impeller performance. The results show that pressure losses in the inlet plenum could be reduced by up to 40% with the circumferentially nonuniform designs over the symmetric baseline configuration. Furthermore, a significant reduction in circumferential distortion could be achieved with the circumferentially nonuniform designs. The resulting improvement in impeller performance contributed approximately 40% to the overall efficiency gains for inlet plenum and impeller combined.