Significance: Photothermal optical coherence tomography (PT-OCT) has the promise to offer structural images coregistered with chemical composition information, which can offer a significant impact in early detection of diseases such as atherosclerosis.

Aim: We take the first step in understanding the relation between PT-OCT signals and the endogenous tissue composition by considering the interplay between the opto-thermo-physical properties of tissue as a function of its lipid composition and the ensuing effects on the PT-OCT signals.

Approach: Multiparameter theoretical estimates for PT-OCT signal as a function of composition in a two-component lipid–water model are derived and discussed. Experimental data from various concentrations of lipid in the form of droplets and injections under bovine cardiac muscle align with theoretical predictions.

Results: Theoretical and experimental results suggest that the variations of heat capacity and mass density with tissue composition significantly contribute to the amount of optical path length difference measured by OCT phase.

Conclusion: PT-OCT has the potential to offer key insights into the chemical composition of the subsurface lipid pools in tissue; however, the interpretation of results needs to be carried out by keeping the nonlinear interplay between the tissue of opto-thermo-physical properties and PT-OCT signals in mind.