Abstract To better understand the relationship between baseline immunoglobulin measurements and subsequent clinical outcomes in chronic lymphocytic leukemia (CLL), we performed a retrospective analysis on 660 patients with CLL (72%), monoclonal B-cell lymphocytosis (MBL) (13%), and small lymphocytic lymphoma (SLL) (14%), diagnosed between 2005 and 2014 at CancerCare Manitoba. Of 511 patients who had their first immunoglobulin level determined within 3 months of diagnosis, abnormal (either increased or decreased) immunoglobulin M (IgM), IgG, and IgA values were observed in 58% of patients with CLL, 27% of patients with MBL, and 20% of patients with SLL. Immunoglobulin deviances were similar for MBL and CLL Rai stage 0 and for SLL and Rai stages I and II; for CLL, IgG and IgA abnormalities occurred with increasing frequency with advancing Rai stage. In contrast, the frequency of IgM abnormalities was similar in all patient groups. IgA abnormalities significantly correlated with high β2-microglobulin (B2M) expression, whereas abnormal IgG and IgA levels were associated with the use of IGHV1-69, 3-21, and 3-49 subtypes. Increases in IgG or IgM were commonly associated with the presence of a CLL-type M-band, whereas oligoclonal bands were frequently observed with increased IgA levels. Although abnormal levels of IgG and IgA at diagnosis were independent predictors for future immunoglobulin replacement, only abnormal IgA levels were associated with shorter time to first treatment and overall survival. These findings indicate that both reduced and elevated levels of IgG and IgA at diagnosis are important and independent prognostic markers for infection in CLL, with IgA being more relevant as a marker of disease progression and survival.