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ABSTRACT: Objectives: Elderly become more susceptible to lower respiratory tract infections, resulting in antibiotic prescriptions. Immunoglobulins (Ig) play an important role in host defense and protection against infections. Therefore, we aimed to investigate whether lower Ig levels are a risk factor for antibiotic use in the general elderly population. Methods: After exclusion of current antibiotic users, Cox proportional-hazards regression models were performed to investigate the effect of stable serum IgM, IgG and IgA levels on time to first antibiotic prescription within the Rotterdam Study. Regression models were adjusted for age, sex, body mass index, smoking status and diabetes. We introduced quadratic terms and additionally categorized Igs to explore and quantify potential non-linearity of the association. The restricted cubic splines technique was used to plot the natural log of the hazard across Ig level. Results: In total, 8,639 participants were included (mean age 64 years, 57% female, medium follow-up 3.2 years). No significant association between IgM and time to antibiotic prescription was observed. IgG and IgA levels (in g/L) showed a U-shaped relationship with time to antibiotic prescription (linear IgG HR 0.959, 95% CI 0.930–0.989; quadratic IgG² HR 1.002, 95% CI 1.000–1.003; linear IgA HR 0.949, 95% CI 0.910–0.990; quadratic IgA² HR 1.009, 95% CI 1.004–1.013). Conclusion: Both low and high IgG and IgA levels were associated with a higher incidence of antibiotic prescriptions in stable middle-aged and older individuals. Increased awareness for the potential increased infection risk when persons have low or high Ig levels, even within the reference ranges, is needed.