The objective of this study was to examine whether greater adoption of Colombia’s Simple Taxation Regime was associated with subsequent changes in multidimensional business informality in Barranquilla, Cartagena, Santa Marta, and Valledupar, while distinguishing participation in a simplified tax regime from substantive business formalization. A balanced quarterly synthetic panel covering 2021Q1–2024Q4 was calibrated to verified annual benchmarks published by the Colombian tax authority and the national statistical agency. The resulting dataset contained 64 city-quarter observations. Calibration consistency and median absolute deviation screening were used as data-verification procedures. The study hypothesis was examined through lagged Spearman correlation, two-way fixed-effects models, and first-difference estimations, with unemployment and service-sector composition included as limited time-varying controls. Calibration discrepancies remained small, while anomaly screening identified four unusually rapid transitions that were retained for analysis. Lagged Spearman and first-difference estimates were generally negative but statistically imprecise. In contrast, fixed-effects coefficients were positive and close to conventional significance thresholds, indicating that the estimated relationship was sensitive to the source of within-city variation used in each specification. The calibrated evidence does not establish a stable association between greater RST intensity and lower multidimensional business informality. Tax-regime uptake, fiscal registration, and broader organizational formalization appear to be related but distinct processes whose trajectories may differ across territories and periods. The study separates simplified-tax participation from substantive formalization and evaluates one hypothesis through complementary longitudinal procedures. It also provides a replicable analytical framework that can later be applied to linked administrative data.