Background <p>Hospitalised COVID-19 patients are susceptible to co-infections. This study aims to evaluate the risk factors and outcomes of secondary co-infections in hospitalised COVID-19 patients in Malaysia. A total of 929 COVID-19 patients were admitted to our centre from January 2021 to December 2022. Thirty-four cases of secondary co-infections among hospitalised COVID-19 patients were identified using standard microbiology culture. A control group of 136 hospitalised COVID-19 patients without secondary infections, admitted during the same period, was randomly selected. Additionally, 48 archived COVID-19 samples were analysed for primary co-infections involving 33 respiratory pathogens using multiplex real-time reverse transcription polymerase chain reaction (RT-PCR).</p> Results <p>The prevalence of secondary co-infections in hospitalised COVID-19 patients was 3.7%. Thirty-nine pathogens were isolated where <i>Acinetobacter baumannii</i> and <i>Candida spp.</i> were among the commonest isolated pathogens (4 isolates each, 10.3%). Significant factors associated with secondary co-infections included longer hospital stay (<i>p</i> ≤ 0.001) and hypertension (<i>p</i> = 0.032). Laboratory findings associated with secondary co-infections were thrombocytopenia (<i>p</i> = 0.021) and elevated alkaline phosphatase (<i>p</i> = 0.024). Among patients with secondary co-infections, 52.9% died, compared to only 14.7% in the control group (<i>p</i> = 0.008), highlighting the poor clinical outcomes of patients with co-infections. Secondary co-infections were also significantly associated with ICU admission (<i>p</i> = 0.045). Out of 48 archived samples, 32 samples (66.7%) were found to have positive respiratory pathogens of primary co-infection.</p> Conclusion <p>Although secondary co-infections occurred in a relatively small subset of hospitalised COVID-19 patients, their profound association with fatal outcomes underscores the need for heightened clinical vigilance when these specific risk factors are present.</p>