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Several causes may lead to CRC, either extrinsic (sporadic forms) or genetic (hereditary forms), such as Lynch syndrome (LS). Most sporadic deficient mismatch repair (dMMR) CRC cases are characterized by the methylation of the <i>MLH1</i> promoter gene and/or <i>BRAF</i> gene mutations. Usually, the first test performed is the mismatch repair deficiency analysis. If a tumor shows a dMMR, <i>BRAF</i> mutations and then the <i>MLH1</i> promoter methylation status have to be assessed, according to the ACG/ASCO screening algorithm. In this study, 100 consecutive formalin-fixed and paraffin-embedded samples of dMMR CRC were analyzed for both <i>BRAF</i> mutations and <i>MLH1</i> promoter methylation. A total of 47 (47%) samples were <i>BRAF</i> p.V600E mutated, while <i>MLH1</i> promoter methylation was found in 77 cases (77.0%). The pipeline “BRAF-followed-by-MLH1-analysis” led to a total of 153 tests, while the sequence “MLH1-followed-by-BRAF-analysis” resulted in a total of 123 tests. This study highlights the importance of performing <i>MLH1</i> analysis in LS screening of <i>BRAF</i>-WT specimens before addressing patients to genetic counseling. We show that <i>MLH1</i> analysis performs better as a first-line test in the screening of patients with LS risk than first-line <i>BRAF</i> analysis. Our data indicate that analyzing <i>MLH1</i> methylation as a first-line test is more cost-effective.