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Abstract. Hypolimnetic oxygen depletion during summer stratification in lakes can lead to hypoxic and anoxic conditions. Hypolimnetic anoxia is a water quality issue with many consequences, including reduced habitat for cold-water fish species, reduced quality of drinking water, and increased nutrient and organic carbon (OC) release from sediments. Both allochthonous and autochthonous OC loads contribute to oxygen depletion by providing substrate for microbial respiration; however, their relative contributions to oxygen depletion across diverse lake systems remain uncertain. Lake characteristics, such as trophic state, hydrology, and morphometry, are also influential in carbon-cycling processes and may impact oxygen depletion dynamics. To investigate the effects of carbon cycling on hypolimnetic oxygen depletion, we used a two-layer process-based lake model to simulate daily metabolism dynamics for six Wisconsin lakes over 20 years (1995–2014). Physical processes and internal metabolic processes were included in the model and were used to predict dissolved oxygen (DO), particulate OC (POC), and dissolved OC (DOC). In our study of oligotrophic, mesotrophic, and eutrophic lakes, we found autochthony to be far more important than allochthony to hypolimnetic oxygen depletion. Autochthonous POC respiration in the water column contributed the most towards hypolimnetic oxygen depletion in the eutrophic study lakes. POC water column respiration and sediment respiration had similar contributions in the mesotrophic and oligotrophic study lakes. Differences in terms of source of respiration are discussed with consideration of lake productivity and the processing and fates of organic carbon loads.