In quantitative mass spectrometry imaging (MSI), the gold standard adds a single structural homologue of the target compound at a known concentration to the sample. This internal standard enables to map the detected intensity of the target molecule against an external calibration curve. This approach, however, ignores local noise levels and disproportional ion suppression effects, which might depend on the concentration of the target compound. To overcome these issues, we propose a novel approach that applies several isotopically labeled versions, each at a different concentration, to the sample. This allows creating individual internal calibration curves for every MSI pixel. As proof of principle, we have quantified an endogenous peptide of histone H4 by matrix-assisted laser desorption/ionization-Q-MSI (MALDI-Q-MSI), using a mixture of three isotopically labeled versions. The usage of a fourth label allowed us to compare the gold standard to our multilabel approach. We observed substantial heterogeneity in ion suppression across the tissue, which disclosed itself as varying slopes in the per-pixel regression analyses. These slopes were histology-dependent and differed from each other by up to a factor of 4. The results were validated by liquid chromatography-mass spectrometry (LC-MS), exhibiting a high agreement between LC-MS and MALDI-Q-MSI (Pearson correlation r = 0.87). A comparison between the multilabel and single-label approaches revealed a higher accuracy for the multilabel method when the local target compound concentration differed too much from the concentration of the single label. In conclusion, we show that the multilabel approach provides superior quantitation compared to a single-label approach, in case the target compound is inhomogeneously distributed at a wide concentration range in the tissue.