In the context of the anaerobic digestion of slowly biodegradable substrates for energy and chemicals production, this study investigated the anaerobic digestion of cellulose without any chemical pre-treatments using open (undefined) mixed microbial cultures. The anaerobic conversion of cellulose was investigated in extended-length (run length in the range 518–734 days) batch and semi-continuous runs (residence time 20–80 days), at high cellulose concentration (20–40 g L−1), at temperatures of 25 and 35 °C. The maximum cellulose removal was 77% in batch (after 412 days) and 60% (at 80 days residence time) in semi-continuous experiments. In semi-continuous experiments, cellulose removal increased as the residence time increased however the cellulose removal rate showed a maximum (0.17 g L−1 day−1) at residence time 40–60 days. Both cellulose removal and removal rate decreased when cellulose concentration in the feed was increased from 20 to 40 g L−1. Liquid-phase products (ethanol and short chain organic acids) were only observed under transient conditions but not at the steady state of semi-continuous runs. Most of the observed results were well described by a mathematical model which included cellulose hydrolysis and growth on the produced glucose. The model provided insight into the physical phenomena behind the observed results.