Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial. Prior covalent BTKi therapy was allowed, but not prior treatment with venetoclax. Patients were assigned to receive PV (n = 15) or PVR (n = 10) for 25 cycles. Most patients (68%) had received prior covalent BTKi therapy. At the data cutoff date, the median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% confidence interval [CI], 68.1-99.8) for PV and 100% (95% CI, 69.2-100.0) for PVR, with 10 complete responses (PV: 7; PVR: 3). After 12 cycles of treatment, 85.7% (95% CI, 57.2-98.2) of PV and 90.0% (95% CI, 55.5-99.7) of PVR patients achieved undetectable minimal residual disease (<10-4) in peripheral blood. Progression-free survival at 18 months was 92.9% (95% CI, 59.1-99.0) for PV patients and 80.0% (95% CI, 40.9-94.6) for PVR patients. No dose-limiting toxicities were observed during the 5-week assessment period. The most common grade ≥3 adverse events (AEs) for all patients included neutropenia (52%) and anemia (16%). AEs led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529.