Computational analysis of shotgun proteomics data can now be performed in a completely automated and statistically rigorous way, as exemplified by the freely available MaxQuant environment. The sophisticated algorithms involved and the sheer amount of data translate into very high computational demands. Here we describe parallelization and memory optimization of the MaxQuant software with the aim of executing it on a large computer cluster. We analyze and mitigate bottlenecks in overall performance and find that the most time-consuming algorithms are those detecting peptide features in the MS(1) data as well as the fragment spectrum search. These tasks scale with the number of raw files and can readily be distributed over many CPUs as long as memory access is properly managed. Here we compared the performance of a parallelized version of MaxQuant running on a standard desktop, an I/O performance optimized desktop computer ("game computer"), and a cluster environment. The modified gaming computer and the cluster vastly outperformed a standard desktop computer when analyzing more than 1000 raw files. We apply our high performance platform to investigate incremental coverage of the human proteome by high resolution MS data originating from in-depth cell line and cancer tissue proteome measurements.