Ancillary molecular testing has been advocated for diagnostic accuracy in the differentiation of lipomas from atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDL); however, the implications and specific indications for use are not well-established in the current literature. Herein, we extend previous findings by quantitatively evaluating the impact of molecular testing of lipomatous neoplasms in our routine clinical practice, how it modifies the historical perspective of their clinical course, and the effect of distinct surgical procedures in modulating the risk of local recurrence for these tumors after molecular classification. On the basis of these analyses, we suggest a specific set of basic recommendations for complementary molecular assessment in the diagnosis of lipomatous tumors. Four hundred and five lipomatous neoplasms located in the trunk and extremities were analyzed histologically and for the presence of 12q13-15 amplification on paraffin-embedded tissues by assessing MDM2/CPM amplification. Survival analyses were calculated with Kaplan-Meier and compared with the log-rank. Multivariate analysis was evaluated by the Cox regression method. The 405 tumors were histologically classified as ordinary lipoma (n=324), intramuscular lipoma (n=29), and ALT/WDL (n=52). The level of agreement between the histologic diagnosis and the molecular diagnosis was high (96%) but pathologists showed a tendency to overestimate cytologic atypia and the diagnosis of ALT/WDL (precision, 79%; accuracy, 88%). Molecular assessment led to a major diagnostic reclassification in 18 tumors (4%). Eleven of the tumors histologically classified as ALT/WDL were reclassified as ordinary lipoma (n=5) and intramuscular lipoma (n=6); none of which recurred. Seven ordinary lipomas were reclassified as ALT/WDL, 6 of which were larger than 15 cm and deeply located; 2 recurred locally. After molecular data, the 5-year local recurrence rates for ordinary lipoma, intramuscular lipoma, and ALT/WDL were 1%, 12%, and 44%, respectively. Multivariate analyses after molecular assessment showed tumor type and type of resection to be associated with the risk of local recurrence. Complementary molecular testing refines the histologic classification of lipomatous tumors and better estimates the impact of surgical procedures on the risk of local recurrence. Pathologists tend to overestimate the degree of cytologic atypia and the indiscriminate use of molecular testing should be avoided, especially for extremity-based tumors. Molecular testing should be considered for "relapsing lipomas," tumors with questionable cytologic atypia (even if widely excised), or for large lipomatous tumors (>15 cm) without diagnostic cytologic atypia.