Background <p>Important protocol deviations (PDs) are those that may significantly impact the completeness, accuracy, or reliability of study data, or that may significantly affect a subject’s rights, safety, or well-being. There is limited international evidence about the incidence and characterization of important PDs, with a lack of data specific to Latin America.</p> Methods <p>This was a non-interventional, secondary data, observational study based on important PDs reported in phase 2–3 clinical trials. Data were collected from electronic reports submitted between 2014 and 2024 to the Independent Ethics Committee (IEC). The main objective was to assess the incidence and characterize important PDs. A secondary objective was to evaluate possible factors associated with the incidence of important PDs.</p> Results <p>A total of 343 clinical trials, involving 7047 randomized participants, were included in the observational period. The overall proportion of patients with important PDs was 9.2% (95% CI: 8.54–9.9%). The primary factor associated with the number of important PDs was the number of randomized patients (Incidence Rate Ratio [IRR]: 1.01; 95% CI: 1–1.02; <i>p</i> &lt; 0.05). A trend was observed for the disease category, with oncology studies tending toward a higher incidence compared to non-oncology studies (IRR: 1.81; 95% CI: 0.92–3.84; <i>p</i> = 0.09).</p> Conclusions <p>The overall incidence of important PDs in this study was low, with the highest proportion observed in oncology studies. Important PDs were significantly associated with the number of randomized patients and showed a trend toward association with more complex oncology studies.</p>