Calcium ion (Ca2+) imbalance is a potential trigger for apoptosis and has been implicated in Alzheimer’s disease. Carbon monoxide (CO) gas has recently been shown to provide neuroprotection against amyloid beta (Aβ1-42) peptide (1). Our study aimed to investigate the interplay between intracellular Ca2+ and Aβ1-42 in microglia cells. Using the BV-2 microglia cell line we determined cell viability and intracellular calcium concentrations in the presence of Aβ1-42 alone and in addition of the carbon monoxide releasing molecule (CORM-2). Cell viability XTT assays showed that Aβ1-42 (48hrs) displayed no microglia toxicity using a range of concentrations (100pM-1µM, 1µM : 94.8 ± 1.1 % cell viability, mean ± SEM, P>0.05, Student’s paired t test, n=48 from 4 replicates). Further viability studies revealed that CORM-2 (1µM-100µM) was also not toxic to microglia cells (116 ± 12% cell viability, P>0.05, Student’s paired t test, n=24 from 2 replicates). To investigate intracellular Ca2+ levels we employed the Fluo-4 fluorescent probe. BV-2 cells pre-exposed to Aβ1-42 peptide showed a dose dependent increase in intracellular Ca2+ levels, significant at 1µM (12.4 ± 1.5% increase, P<0.05, Student’s paired t test, n=100 from 10 replicates). This increase was not observed in the presence of a scrambled Aβ peptide (0.5 ± 0.01% increase, P>0.05, Student’s paired t test, n=40 from 4 replicates), highlighting specificity for Aβ1-42. Interestingly in the presence of 10µM CORM-2, the Aβ1-42 induced intracellular Ca2+ rise was significantly suppressed (112.4 ± 1.5% reduced to 96 ± 2.5% in the presence of CORM-2, P<0.05, Student’s paired t test, n=20 from 4 replicates). Further experiments using the inactive form of CORM (iCORM) failed to suppress the increase in intracellular Ca2+ levels in the presence of 1µM Aβ1-42 (15.6 ± 1.6%, P>0.05, Student’s paired t test, n=20 from 4 replicates) suggesting that suppression was predominantly mediated by CO. These results highlight the potential for CO to be used to modulate microglia physiology to provide a novel approach in tackling neurodegenerative diseases.