Monoclonal antibodies (MAbs) usually display slow and limited distribution with combined linear and non-linear elimination mechanisms. While studying individual pharmacokinetic profiles, it was noticed that MAb plasma concentration can vary abruptly over time, with one or more increases after the time to maximum plasma concentration when theoretically the concentration should only decline. This article summarizes the frequency of these additional peaks and assesses whether normal intra-subject and assay variability can explain the observations. For this analysis, we used a benchmark consisting of three registered (adalimumab, bevacizumab, and trastuzumab) and three unregistered immunoglobulin G1 MAbs. At a selected 'normal' intra-subject variability of 12%, at least 70% of the study participants (approximately 90% for certain MAbs) still had at least one additional peak, which decreased when the 'normal' variability was increased. There was no difference in occurrence between the high- and low-concentration ranges. Only a high sample density was associated with an increased likelihood of detecting additional peaks. Based on the analytical variability for the applied ligand-binding assays (5-10%, up to 15% at the lower limit of quantitation), the number of observed increases was extremely improbable (p < 0.01) for most MAbs, especially for the large excursions. Therefore, the fluctuations are likely genuine. We discuss the possible explanations and the relevance for clinical practice.