Objectives <p>HHIP-AS1 is a lncRNA located at the HHIP gene locus that has been previously implicated in cancer-related pathways. Nevertheless, the expression pattern and clinical relevance of HHIP-AS1 in AML remain unclear. The current study examined HHIP-AS1 expression status and its clinical significance in non-M3 AML patients.</p> Methods <p>Quantitative reverse transcription–polymerase chain reaction was performed to evaluate HHIP-AS1 transcription profiles in 60 non-M3 AML patients compared with 49 control subjects. The correlation between HHIP-AS1 expression and clinicopathological parameters was then statistically examined.</p> Results <p>Analysis showed that non-M3 AML patients have lower HHIP-AS1 transcript levels than healthy volunteers (p &lt; 0.001). Subsequently, patients were divided into HHIP-AS1 high-expressing (HHIP-AS1^high) and low-expressing (HHIP-AS1^low) groups based on the median HHIP-AS1 expression level. The HHIP-AS1^low group tended to have a higher blast percentage and a higher peripheral white blood cell count and had notably shorter OS and RFS (p = 0.013 and 0.004, respectively). Moreover, patients with lower initial HHIP-AS1 expression had a refractory response to chemotherapies. Multivariate analysis confirmed the significant association between low HHIP-AS1 expression on both OS and RFS.</p> Conclusions <p>Our study suggests that downregulation of HHIP-AS1 expression is an independent poor prognostic factor and a diagnostic biomarker in non-M3 AML patients.</p>