Objective: To estimate the association between immunologic response to antiretroviral therapy (ART) and non-AIDS defining cancer (NADC) incidence in HIV-infected patients. Design: A prospective cohort including patients with at least 1 cell/ml CD4+ cell count and HIV-1 RNA measure after ART initiation between 1996 and 2011 in the Centers for AIDS Research Network of Integrated Clinical Systems, a collaboration of eight HIV clinics at major academic medical centres in the United States. Methods: Measures of immunologic response were 6-month CD4+ post-ART, latest CD4+ and CD4+ count-years, a cumulative measure of CD4+ lymphopenia. Cox regression with inverse probability-of-exposure weights was used to calculate adjusted hazard ratios of virus-related and virus-unrelated NADC incidence. Results: Among 9389 patients at ART initiation, median CD4 + cell count was 200 cells/ml [interquartile range (IQR) 60-332)], and median HIV-1 RNA was 4.8 log10copies/ml (IQR 4.3-5.4). Median follow-up was 3.3 years (IQR 1.5-6.5). After 6 months of ART, median CD4+ cell count was 304 cells/ml (IQR 163-469). One hundred and sixty-four NADCs were diagnosed during study follow-up, 65 (40%) considered virus-related. Virus-related NADCs were inversely associated with 6-month CD4+ cell count (hazard ratio per 100 cells/ml increase1/40.71), latest CD4+ cell count (hazard ratio per 100 cells/ml increase1/40.70) and CD4+ cell count-years (hazard ratio per 200 cellyears/μl increase=0.91) independent of CD4+ cell count at ART initiation, age and HIV-1 RNA response. No associations were found with virus-unrelated NADCs. Conclusion: Poor CD4+ cell count response was strongly associated with virus-related NADC incidence, suggesting an important role for T-cell mediated immunity in pathogenesis. Lower CD4+ cell count proximal to cancer diagnosis may be a result of subclinical cancer. Intensified cancer screening should be considered for patients on ART with low CD4+ cell counts. © 2014 Wolters Kluwer Health.