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Abstract We explore the relationship between mid-infrared (mid-IR) and CO rotational line emission from massive star-forming galaxies, which is one of the tightest scalings in the local universe. We assemble a large set of unresolved and moderately (∼1 kpc) spatially resolved measurements of CO (1–0) and CO (2–1) intensity,I_CO, and mid-IR intensity,I_MIR, at 8, 12, 22, and 24μm. TheI_COversusI_MIRrelationship is reasonably described by a power law with slopes 0.7–1.2 and normalizationI_CO∼ 1 K km s⁻¹atI_MIR∼ 1 MJy sr⁻¹. Both the slopes and intercepts vary systematically with choice of line and band. The comparison between the relations measured for CO (1–0) and CO (2–1) allow us to infer that $R_{21}\propto I_{\mathrm{MIR}}^{0.2}$, in good agreement with other work. The 8μm and 12μm bands, with strong polycyclic aromatic hydrocarbon (PAH) features, show steeper CO versus mid-IR slopes than the 22 and 24μm, consistent with PAH emission arising not just from CO-bright gas but also from atomic or CO-dark gas. The CO-to-mid-IR ratio correlates with global galaxy stellar mass (M_⋆) and anticorrelates with star formation rate/M_⋆. At ∼1 kpc resolution, the first four PHANGS–JWST targets show CO-to-mid-IR relationships that are quantitatively similar to our larger literature sample, including showing the steep CO-to-mid-IR slopes for the JWST PAH-tracing bands, although we caution that these initial data have a small sample size and span a limited range of intensities.