Co-current two-phase simulations of gas-liquid flow with mixture velocities from 1.2 to 4.2 m/s were run in a partially eccentric annulus and compared with entirely eccentric and concentric experimental data collected at the Institute for Energy Technology in Norway. The gas-phase was sulphur hexafluoride (SF6) for all cases, while the liquid-phase was Exxsol D60 for the horizontal cases and a mixture of Exxsol D60 and Marcol 82 for the inclined case. The outer diameter of the annulus was 0.1 m for all cases, while the inner diameter was 0.05 m in the horizontal configuration and 0.04 m for the inclined configuration. The purpose of this paper is to explore the effect of the holdup fraction, mixture velocity, and interior pipe’s position on the pressure gradient and flow regime, in effect a study of the pressure gradient and holdup fraction transients. The comparisons between simulations and experiments indicate that moving the pipe from an entirely eccentric to the partially eccentric configuration has a drastic impact on the pressure gradient. In all 4 cases where the inner pipe was changed from a completely eccentric geometry in the experiments to a less eccentric configuration in the simulations, we notice an increase of 48–303% of the mean pressure gradient. Comparatively, the 4 cases where the pipe was moved from a concentric experimental configuration to a more eccentric configuration in the simulations result in less drastic pressure gradient changes. Two cases were within 22% of the experimental results for mean, maximum, and minimum pressure gradient, while the last two cases exceeded the minimum and mean pressure gradients by 25–250%, respectively. The flow regime is rarely significantly affected by a change in eccentricity; 2 out of the 8 horizontal cases indicate either a transition from wavy flow to slug flow or significantly larger waves. The most prominent and frequent discrepancies identified were altered slug and wave frequencies. The last case, a 4o inclined, partially eccentric simulation was compared to an entirely eccentric experiment and results in a 0.2 Hz increase in wave frequency, up from the experimental 0.56 Hz and a 49% increase in the mean pressure gradient.