Physiological fluctuations are expected to be a dominant source of noise in blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) experiments to assess tumour oxygenation and angiogenesis. This work investigates the impact of various physiological noise regressors: retrospective image correction (RETROICOR), heart rate (HR) and respiratory volume per unit time (RVT), on signal variance and the detection of BOLD contrast in the breast in response to a modulated respiratory stimulus. BOLD MRI was performed at 3 T in ten volunteers at rest and during cycles of oxygen and carbogen gas breathing. RETROICOR was optimized using F-tests to determine which cardiac and respiratory phase terms accounted for a significant amount of signal variance. A nested regression analysis was performed to assess the effect of RETROICOR, HR and RVT on the model fit residuals, temporal signal-to-noise ratio, and BOLD activation parameters. The optimized RETROICOR model accounted for the largest amount of signal variance ([Formula: see text] = 3.3 ± 2.1%) and improved the detection of BOLD activation (P = 0.002). Inclusion of HR and RVT regressors explained additional signal variance, but had a negative impact on activation parameter estimation (P