Gamma-ray detectors based on thick monolithic scintillator crystals can achieve spatial resolutions <2 mm full-width-at-half-maximum (FWHM) and coincidence resolving times (CRTs) better than 200 ps FWHM. Moreover, they provide high sensitivity and depth-of-interaction (DOI) information. While these are excellent characteristics for clinical time-of-flight (TOF) positron emission tomography (PET), the application of monolithic scintillators has so far been hampered by the lengthy and complex procedures needed for position- and time-of-interaction estimation. Here, the algorithms previously developed in our group are revised to make the calibration and operation of a large number of monolithic scintillator detectors in a TOF-PET system practical. In particular, the k-nearest neighbor (k-NN) classification method for x,y-position estimation is accelerated with an algorithm that quickly preselects only the most useful reference events, reducing the computation time for position estimation by a factor of ~200 compared to the previously published k-NN 1D method. Also, the procedures for estimating the DOI and time of interaction are revised to enable full detector calibration by means of fan-beam or flood irradiations only. Moreover, a new technique is presented to allow the use of events in which some of the photosensor pixel values and/or timestamps are missing (e.g. due to dead time), so as to further increase system sensitivity. The accelerated methods were tested on a monolithic scintillator detector specifically developed for clinical PET applications, consisting of a 32 mm × 32 mm × 22 mm LYSO : Ce crystal coupled to a digital photon counter (DPC) array. This resulted in a spatial resolution of 1.7 mm FWHM, an average DOI resolution of 3.7 mm FWHM, and a CRT of 214 ps. Moreover, the possibility of using events missing the information of up to 16 out of 64 photosensor pixels is shown. This results in only a small deterioration of the detector performance.