Cancer drug prescribing by medical oncologists accounts for the greatest variation in practice and the largest portion of spending on cancer care. We evaluated the association between a national commercial insurer's ongoing pay-for-performance (P4P) program for oncology and changes in the prescribing of evidence-based cancer drugs and spending.We conducted an observational difference-in-differences study using administrative claims data covering 6.7% of US adults. We leveraged the geographically staggered, time-varying rollout of the P4P program to simulate a stepped-wedge study design. We included patients age 18 years or older with breast, colon, or lung cancer who were prescribed cancer drug regimens by 1,867 participating oncologists between 2013 and 2017. The exposure was a time-varying dichotomous variable equal to 1 for patients who were prescribed a cancer drug regimen after the P4P program was offered. The primary outcome was whether a patient's drug regimen was a program-endorsed, evidence-based regimen. We also evaluated spending over a 6-month episode period.The P4P program was associated with an increase in evidence-based regimen prescribing from 57.1% of patients in the preintervention period to 62.2% in the intervention period, for a difference of +5.1 percentage point (95% CI, 3.0 percentage points to 7.2 percentage points; P < .001). The P4P program was also associated with a differential $3,339 (95% CI, $1,121 to $5,557; P = .003) increase in cancer drug spending and a differential $253 (95% CI, $100 to $406; P = .001) increase in patient out-of-pocket spending, but no significant changes in total health care spending ($2,772; 95% CI, -$181 to $5,725; P = .07) over the 6-month episode period.P4P programs may be effective in increasing evidence-based cancer drug prescribing, but may not yield cost savings.