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Hybrid proline-rich proteins (HyPRPs) belong to the family of 8-cysteine motif (8CM) containing proteins that play important roles in plant development processes, and tolerance to biotic and abiotic stresses. To gain insight into the rice HyPRPs, we performed a systematic genome-wide analysis and identified 45 <i>OsHyPRP</i> genes encoding 46 OsHyPRP proteins. The phylogenetic relationships of OsHyPRP proteins with monocots (maize, sorghum, and <i>Brachypodium</i>) and a dicot (Arabidopsis) showed clustering of the majority of OsHyPRPs along with those from other monocots, which suggests lineage-specific evolution of monocots HyPRPs. Based on our previous RNA-Seq study, we selected differentially expressed <i>OsHyPRPs</i> genes and used quantitative real-time-PCR (qRT-PCR) to measure their transcriptional responses to biotic (<i>Magnaporthe</i> <i>oryzae</i>) and abiotic (heat, cold, and salt) stresses and hormone treatment (Abscisic acid; ABA, Methyl-Jasmonate; MeJA, and Salicylic acid; SA) in rice blast susceptible Pusa Basmati-1 (PB1) and blast-resistant near-isogenic line PB1+<i>Pi9</i>. The induction of <i>OsHyPRP16</i> expression in response to the majority of stresses and hormonal treatments was highly correlated with the number of <i>cis</i>-regulatory elements present in its promoter region. <i>In silico</i> docking analysis of OsHyPRP16 showed its interaction with sterols of fungal/protozoan origin. The characterization of the <i>OsHyPRP</i> gene family enables us to recognize the plausible role of <i>OsHyPRP16</i> in stress tolerance.