Background <p>In recent years, alternating epidemics of multiple respiratory pathogens have appeared globally, with recurrent infections in some individuals. However, there is a lack of evidence from clinical studies on the effects of the initial pathogen on the incidence, severity, and regression of infections with the subsequent pathogen. This study involved college students as survey respondents during the successive outbreaks of <i>Mycoplasma pneumoniae</i> (MP) and influenza epidemics to obtain evidence regarding MP–influenza interference.</p> Methods <p>MP and influenza epidemics occurred successively between September 2023 and February 2024. Internet-based questionnaires were administered to all freshmen enrolled in August 2023 at three closed-management public universities in northern China after the end of the first wave of the MP epidemic and the second wave of the influenza epidemic, respectively. The participants self-rated their perceived severity for 16 symptoms, and the scores were summed to obtain a combined symptom score for each individual. Multiple logistic and linear regression analyses were used to investigate the effect of previous MP infection on the incidence and severity of subsequent influenza infection.</p> Results <p>A total of 1803 cases of MP-like illness and 2111 cases of influenza-like illness (ILI) were observed among 5790 freshmen across two waves of respiratory infection outbreaks. Moreover, 709 and 1244 cases were voluntarily tested for pathogens at the university clinic, of which 549 (77.4%) and 1035 (83.2%) cases were finally confirmed as having MP and influenza virus infections, respectively. The ILI infection rate after MP-like illness was higher than that among students without MP-like illness [39.3% (708/1803) vs. 35.2% (1403/3987), <i>P</i> = 0.003]. Multivariate logistic regression analysis showed that previous confirmed MP infection was significantly associated with the development of subsequent influenza infection (odds ratio: 1.321; 95% confidence interval: 1.214–1.451; <i>P</i> &lt; 0.001). Furthermore, multiple linear regression models revealed that previous MP infection was an independent predictor of a higher symptom severity score for influenza infection (adjusted β = 0.137, <i>P</i> &lt; 0.001).</p> Conclusions <p>Recent infection with MP may be associated with an increased rate of subsequent influenza infection. Moreover, previous MP infection was a predictor of higher symptom severity during subsequent influenza infection.</p> Clinical trial number <p>Not applicable.</p>