Background:  Homologous recombination deficiency (HRD), often resulting from mutations in the BRCA1/2 genes, forces cancer cells to utilize alternative, mutagenic pathways to repair DNA double-strand breaks (DSBs). Ovarian cancer (OV) is one of the cancers most affected by this mechanism. In HRD tumors, cells use a mechanism called microhomology-mediated end-joining (MMEJ), which involves the use of short homologous sequences to rejoin damaged DNA. The aim of this study was to characterize the genomic consequences and determinants of MMEJ activity in HRD-affected cancers. The analysis included Whole-Genome Sequencing (WGS, n = 121) and Whole-Exome sequencing (WES, n = 506) data for OV, as well as data from 30 other cancer types (n = 7591). A tool, MHDetect, was developed to classify indels—insertions, deletions, and multinucleotide variants (MNVs)—to identify events potentially generated by MMEJ. WGS and WES data were processed using four tools: Strelka2, MuTect2, Pindel, and VarScan2. The analysis focused on the frequency of MMEJ-dependent deletions, with a particular focus on ovarian cancer. The number of deletions in samples stratified by Loss-of-Function variants was compared using the Wilcoxon test to identify genes with significant differences. We observed significant variation in MMEJ pathway activity across different tumor types. The highest frequencies of MMEJ-associated deletions were found in TGCT (testicular germ cell tumors), PCPG (pheochromocytomas and paragangliomas), and THCA (thyroid cancer). In ovarian cancer, an increased number of MMEJ-dependent deletions was particularly associated with loss of RB1 function, indicating that MMEJ overactivity is not limited to BRCA1/2 abnormalities. Survival analysis further demonstrated that a higher number of MMEJ-dependent deletions correlates with a better patient prognosis, even in the absence of PARP inhibitor treatment.