Introduction: We aimed to assess the natural annual trends in the levels of haemoglobin, haematocrit, and mean corpuscular volume (MCV) in a population of adults, together with the influence of different clinical parameters on these trends. Methods: A retrospective analysis was carried out on data from a large cohort of subjects attending a screening centre in Israel. For each subject, the yearly average change of haemoglobin, haematocrit, and MCV was calculated. Statistical analysis was performed for the whole cohort and for different subgroups. Results: The study included 3,551 subjects. The average annual rates of decline were found to be −0.0550 g/dL (95% confidence interval [CI] −0.0590 g/dL to −0.0503 g/dL) and −0.097% (95% CI −0.112% to −0.083%) for haemoglobin and haematocrit, respectively. An average annual increase in the MCV level by 0.184 fL (95% CI 0.168 fL–0.200 fL) was found. Among men, the rate of decline in haemoglobin was found to be twice as high compared with women −0.06 g/dL versus −0.03 g/dL, respectively (p = 0.0063). In a multivariate analysis, gender remained the only parameter significantly associated with the annual decline of haemoglobin (p = 0.0001). Conclusion: An annual average decrease in the levels of haemoglobin and haematocrit together with an annual increase in MCV was found. These changes were more prominent in men.