Purpose Achieving biochemical control (normalization of insulin-like growth factor-1 [IGF-1] and growth hormone [GH]) is a key goal in acromegaly management. However, IGF-1 and GH fluctuate over time. The true potential impact of time-varying biochemical control status on comorbidities is unclear and relies on multiple, longitudinal IGF-1 and GH measurements. This study assessed the association between time-varying biochemical control status and onset of selected comorbidities in patients with acromegaly. Methods Medical charts of adults with confirmed acromegaly and ≥ 6 months of follow-up at an Italian endocrinology center were reviewed. Patients were followed from the first diagnosis of acromegaly at the center until loss to follow-up, chart abstraction, or death. Biochemical control status was assessed annually and defined as IGF-1 ≤ the upper limit of normal, or GH ≤ 2.5 µg/L in the few cases where IGF-1 was unavailable. Time-varying Cox models were used to assess the association between biochemical control status and comorbidities. Results Among 150 patients, 47% were female, average age at diagnosis was 43.1, and mean length of follow-up was 10.4 years. Biochemical control was significantly associated with a lower hazard of diabetes (HR = 0.36, 95% CI 0.15; 0.83) and cardiovascular system disorders (HR = 0.54, 95% CI 0.31; 0.93), and a higher hazard of certain types of arthropathy (HR = 1.68, 95% CI 1.04; 2.71); associations for other comorbidities did not reach statistical significance. Conclusion Results further support the importance of achieving biochemical control, as this may reduce the risk of high-burden conditions, including diabetes and cardiovascular system disorders. The association for arthropathy suggests irreversibility of this impairment. Due to limitations, caution is required when interpreting these results.