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Understanding the mechanisms behind critical thermal maxima (CTmax; the high body temperature at which neuromuscular coordination is lost) of organisms is central to understanding ectotherm thermal tolerance. Body size is an often overlooked variable that may affect interpretation of CTmax, and consequently, how CTmax is used to evaluate mechanistic hypotheses of thermal tolerance. We tested the hypothesis that body size affects CTmax and its interpretation in two experimental contexts. First, in four Sceloporus species, we examined how inter‐ and intraspecific variation in body size affected CTmax at normoxic and experimentally induced hypoxic conditions, and cloacal heating rate under normoxic conditions. Negative relationships between body size and CTmax were exaggerated in larger species, and hypoxia‐related reductions in CTmax were unaffected by body size. Smaller individuals had faster cloacal heating rates and higher CTmax, and variation in cloacal heating rate affected CTmax in the largest species. Second, we examined how body size interacted with the location of body temperature measurements (i.e., cloaca vs. brain) in Sceloporus occidentalis, then compared this in living and deceased lizards. Brain temperatures were consistently lower than cloacal temperatures. Smaller lizards had larger brain‐cloacal temperature differences than larger lizards, due to a slower cloacal heating rate in large lizards. Both live and dead lizards had lower brain than cloacal temperatures, suggesting living lizards do not actively maintain lower brain temperatures when they cannot pant. Thermal inertia influences CTmax data in complex ways, and body size should therefore be considered in studies involving CTmax data on species with variable sizes.